JP2013126558A - Sustained drug-releasing stent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a stent carrying a vascular intimal hyperplasia inhibitor which does not inhibit proliferation of endothelial cells, which stent is capable of releasing the drug in controlled manner.SOLUTION: The stent includes: a stent body of a cylindrical configuration having surfaces without a diamond-like thin film coated on the surfaces; a first coated layer coating at least the outer surface of the stent body; and a second coated layer coating substantially completely over the first coated layer. The first coated layer is prepared of a first composition comprising a polymer and a vascular intimal hyperplasia inhibitor which does not inhibit proliferation of endothelial cells, the weight compositional ratio of the polymer to the vascular intimal hyperplasia inhibitor is within the range of 8:2 to 3:7. The second coated layer is prepared of a polymer alone or a second composition comprising a polymer and a drug, the weight compositional ratio of the drug is less than 20 wt.%.

Description

Related applications

  This application claims the priority of Japanese Patent Application No. 2007-228788, filed on Sep. 4, 2007, which is incorporated by reference in its entirety as a part of this application.

  The present invention relates to a sustained drug release stent useful for treatment of a stenotic vasculature, a method for producing the stent, and a method for adjusting the release rate of the drug from the stent. More specifically, the present invention relates to a stent loaded with an intimal thickening inhibitor that does not inhibit endothelial cell proliferation, a method for producing the stent, and a method for adjusting a drug release rate from the stent.

  A stent treatment method that mechanically dilates an arterial lesion that has been narrowed due to the progress of arteriosclerosis with a balloon catheter and restores blood flow by placing a metal stent in the lumen of the artery is rapidly spreading in recent years. It has become. In coronary arteries, which are likely to be life-threatening due to stenosis / occlusion, even if a stent is placed, the intima of the blood vessel will soon thicken, and the lumen secured by the placement of the stent will be narrowed, requiring retreatment. Probability reaches 20-30%. Therefore, in order to suppress stenosis in the stent, an attempt is made to suppress the stenosis by carrying a drug that can be expected to have a stenosis suppressing effect on the stent surface and gradually releasing the drug in the blood vessel, and sirolimus (immunosuppressant) and paclitaxel ( This led to the practical application of a drug release stent (hereinafter sometimes referred to as DES) using an anticancer agent. However, since these drugs act on the cell cycle of vascular cells (endothelial cells, smooth muscle cells) to stop proliferation, they only suppress intimal thickening due to excessive proliferation of smooth muscle cells. In addition to this, the proliferation of endothelial cells detached at the time of stent placement is also suppressed, and the side effect of delaying repair / healing of the blood vessel inner wall occurs. Since blood clots are likely to occur in areas where the inner wall of the blood vessel is not covered with endothelial cells, antithrombotic agents must be taken for a long period of more than half a year, and even if antithrombotic agents are taken, delayed thrombus There is a risk of dysfunction and sudden death.

The first event in the causal relationship from in-stent placement to in-stent stenosis is “injury to blood vessels during stent placement, especially to endothelial cells”, followed by “thrombosis” at the injury site. It is said that a causal relationship is established in the order of “generation”, “adhesion / infiltration of leukocytes into blood vessels”, “inflammation”, “smooth muscle cell proliferation”, and “stenosis”. Therefore, based on the speculation that suppressing thrombus formation is an effective measure for suppressing stenosis, the application of antithrombotic drugs such as heparin and hirudin to drug-releasing stents has been energetically studied in the early stages of development. However, clinical efficacy was not confirmed. As drug-releasing stents using sirolimus paclitaxel have become popular, antithrombotic-coated stents are a minority. Currently, stents drug carrying intimal hyperplasia inhibitor which does not inhibit proliferation of endothelial cells sustained release has not been put into practical use.
On the other hand, Patent Document 1 describes a stent that releases both drugs of argatroban (anticoagulant) and cilostazol (antiplatelet agent). Patent Document 2 describes a drug release rate from a polymer film containing argatroban soaked in a phosphate buffer solution (pH 7.4) for 3 weeks. However, the remarkable intimal thickening suppression effect in the state carried by the stent has not yet been found.

JP 2001-190687 A WO2007 / 058190

  An object of the present invention is to provide a stent that can carry an intimal thickening inhibitor that does not inhibit endothelial cell proliferation and that can gradually release the agent, and a method for producing the stent.

  Another object of the present invention is to provide a method for adjusting the release rate of a drug from a stent.

  A first configuration of the present invention is formed in a cylindrical shape having an outer surface and an inner surface, and the surface of the stent body is not coated with a diamond-like thin film, and covers at least the outer surface of the stent body. A first coating layer, and a second coating layer covering the first coating layer so as to substantially completely cover the first coating layer, the first coating layer comprising a polymer and endothelial cell proliferation A composition having a weight composition ratio of the polymer and the intimal thickening inhibitor in the range of the polymer 8-3 to the intima thickening inhibitor 2-7. And the second coating layer is formed of a polymer alone or contains a polymer and a drug, and the weight composition ratio of the drug to 80% by weight of the polymer is less than 20% by weight. Formed by things And that is a stent.

  In the above-mentioned present invention, the term “stent” means that when a blood vessel or other in-vivo lumen is stenotic or occluded, the stenotic part or the like is expanded to secure a necessary lumen region. This is a tubular medical device to be placed. The stent is inserted into the body with a small diameter and is used to expand the stenosis part to increase the diameter and to hold the lumen part in an expanded state.

  In the present invention, the term “polymer” is used as a term including a homopolymer, a copolymer, or a mixture of polymers.

  In the present invention, the “first composition” and the “second composition” include a polymer and a drug, and the drug is dispersed in a polymer structure (including a dense tissue or a porous tissue) or in a fine solid state. It is what is micro-dispersed. As will be described later, in the first composition, the drug (argatroban) is preferably microdispersed in the polymer structure, and in the second composition, the polymer structure is preferably a dense structure. In the present invention, the “dense tissue” refers to a tissue in which almost no voids are observed in the tissue by observation with an optical microscope.

  In the present invention, as an intimal thickening inhibitor that does not inhibit endothelial cell proliferation, Argatroban, Ximelagatran, Melagatran, Dabigatran, Dabigatran etexilate, and the like are listed. Of these, argatroban is preferable, and argatroban will be described below as an example.

In the present invention, “argatroban” is (2R, 4R) -4-methyl-1- [N ² -((RS) -3-methyl-1,2,3,4) represented by the following chemical structural formula. -Tetrahydro-8-quinolinesulfonyl) -L-arginyl] -2-piperidinecarboxylic acid, hydrate. Argatroban is already known as a compound having an antithrombin action (Patent Documents 1 and 2).

  In the first configuration of the present invention, the thickness of the first coating layer is in the range of 1 to 20 μm, and the thickness of the second coating layer is in the range of 0.5 to 5 μm. preferable.

  Argatroban in the first coating layer is preferably microdispersed in the polymer.

  It is preferable that the first coating layer does not contain any drug other than argatroban.

  The second coating layer is preferably formed from a polymer alone.

  When the second coating layer is formed from the second composition, the drug of the second composition is preferably argatroban, rapamycin, everolimus, biolimus A9, zotarolimus, tacrolimus, paclitaxel or statin.

  The polymer that forms the first composition and / or the second coating layer is preferably a biodegradable polymer.

  The biodegradable polymer is preferably polylactic acid, poly (lactic acid-glycolic acid), polyglycolic acid, poly (lactic acid-ε-caprolactone), or poly (glycolic acid-ε-caprolactone).

  It is preferable that the stent body is formed of a metal material, a ceramic, or a polymer material. In the present invention, the surface of the stent body is not coated with a diamond-like thin film.

  According to a second configuration of the present invention, a stent is prepared by using a solution obtained by dissolving the first composition in a lower alkyl ketone-methanol mixed solvent, a lower alkyl ester-methanol mixed solvent, or a lower halogenated hydrocarbon-methanol mixed solvent. In this stent manufacturing method, at least the outer surface of the main body is coated, and after the coating, the solvent is removed to form the first coating layer.

According to a third configuration of the present invention, in the stent according to the first configuration of the present invention, a thickness of the second coating layer is selected within a range of 0.5 to 5.0 μm. By adjusting the release rate of argatroban on the first day and the second day from the time of immersion of the stent in a phosphate buffered saline solution at 37 ° C. to be 3 μg / cm ² · day or more, respectively. A method for adjusting the release rate of argatroban from a stent.

In the stent according to the first configuration of the present invention described above, the second covering layer has a thickness of 37 ° C. by selecting a predetermined thickness within a range of 0.5 to 5.0 μm. In physiological saline, it is preferable that the release rate of argatroban on the second day from the time of immersion of the stent is in the range of 3 to 100 μg / cm ² · day.

In the stent according to the first configuration of the present invention described above, the second covering layer has a thickness of 37 ° C. by selecting a predetermined thickness within a range of 0.5 to 5.0 μm. It is preferable to adjust the release rate of argatroban in physiological saline from ^{2 to} 50 μg / cm ² · day from the 3rd day to 7th day after the stent is immersed.

  In the first composition, it is preferable that the release rate of argatroban is adjusted by microdispersing argatroban in the polymer.

  The solvent for dissolving the first composition is selected from a lower alkyl ester-methanol mixed solvent, a lower alkyl ketone-methanol mixed solvent, or a lower halogenated hydrocarbon-methanol mixed solvent, and the first solvent is selected according to the selected solvent. It is preferable that the release rate of argatroban is adjusted by coating the surface of the stent body using a solution in which the composition is dissolved, and then removing the solvent to form the first coating layer after coating.

  The polymer of the second coating layer is preferably a poly (lactic acid-glycolic acid) copolymer, and the release rate of argatroban is preferably adjusted by changing the copolymerization ratio of lactic acid and glycolic acid.

  According to a fourth configuration of the present invention, the stent of the first configuration of the present invention is placed in a blood vessel, and argatroban is released from the stent, thereby preventing intimal thickening without inhibiting the proliferation of endothelial cells. It is a method of suppressing.

  According to the first configuration of the present invention, the first coating layer is composed of an intimal thickening inhibitor (preferably argatroban) that does not inhibit the proliferation of endothelial cells and a polymer, and the weight composition ratio thereof is polymer 8-3. The anti-intimal thickening inhibitor is in the range of 2 to 7, and the first covering layer contains a large amount of the intimal thickening inhibitor, and the second covering layer is formed of the polymer alone, or , The second composition comprising a polymer and a drug, wherein the weight ratio of the drug to 80% by weight of the polymer is less than 20% by weight. Since it can be released, it is possible to obtain a stent that can exert the effect of suppressing the intimal thickening without inhibiting the proliferation of endothelial cells. In particular, the second coating layer does not contain or contains a small amount of a drug. In particular, when the second coating layer does not contain a drug, the polymer structure constituting the second coating layer has a high density. Since it is maintained, the release of the drug (argatroban) contained in the first coating layer is suppressed, and the effect of sustained release is great.

  Furthermore, according to the stent of the first configuration of the present invention, the first coating layer has a thickness in the range of 1 to 20 μm, the second coating layer has a thickness in the range of 0.5 to 5 μm, and both layers are combined. However, a thickness of 25 μm or less, preferably 20 μm or less is particularly desirable for preventing stenosis.

  In the second configuration of the present invention, the lower alkyl ketone, lower alkyl ester or lower halogenated hydrocarbon used as the solvent for dissolving the first composition is a solvent for dissolving the polymer, and methanol is a drug (argatroban). It is a solvent that dissolves. By using the mixed solvent, both the polymer and the drug (argatroban) can be dissolved. In the first coating layer formed from the polymer / drug (argatroban) composition formed using this mixed solvent, (Argatroban) is not dissolved (molecularly dispersed) in the polymer of the coating layer, but is micro-dispersed, so that the drug release rate can be easily controlled by controlling the thickness of the second coating layer, etc. Have.

  According to the third configuration of the present invention, in the stent of the first configuration of the present invention, in particular, the first coating containing a high concentration of argatroban (preferably argatroban is microdispersed in the polymer of the first coating layer). By controlling the thickness of the second coating layer formed on the layer to an appropriate thickness within the range of 0.1 to 5 μm, the release rate of argatroban can be adjusted to be within the above range. it can. This makes it possible to obtain a desired release rate.

According to the third configuration of the present invention, argatroban in the covering layer formed on the stent body has a rate of 3 μg / cm ² · day or more over at least 2 days after the stent is placed in a blood vessel, particularly in an artery. Released at. As a result, the pharmacological effect (suppression of intimal thickening) of the released argatroban appears, and the stenosis in the stent is effectively suppressed. Furthermore, one month after the placement of the stent, the endothelial cells cover the entire intimal surface, and as a result, the occurrence of thrombosis, particularly late thrombosis, is reduced compared to existing drug-releasing stents. Has a remarkable effect.

  The drug sustained-release stent of the present invention is effectively used for stent treatment of coronary arteries, but is also effective for stent treatment of cerebral artery, renal artery, and peripheral artery.

The present invention will be clearly understood from the following description of preferred embodiments with reference to the accompanying drawings. However, the embodiments and drawings are merely for illustration and description and should not be used to define the scope of the present invention. The scope of the invention is defined by the appended claims.
It is a perspective view which shows one example of the shape of the stent main body used in this invention. It is a figure which shows the pathological sample of the blood vessel cross section of DES2. It is a figure which shows the pathological sample of the blood vessel cross section of DES5.

(Stent)
The material constituting the stent body is not particularly limited, and conventionally known metal materials, ceramics, and polymer materials are used. Among them, a metal having high rigidity and corrosion resistance is preferable. Specific examples include stainless steel, tantalum, nickel-titanium alloy (including nitinol), magnesium alloy, and cobalt alloy (including cobalt-chromium-nickel alloy). The stent body has a cylindrical shape having an outer surface and an inner surface, and may be a balloon expandable type, a self-expandable type, or a combination thereof. FIG. 1 is a perspective view showing an example of the shape of a stent body used in the present invention, particularly as a drug releasing stent. As for the mesh design of the stent body and the shape of the struts, the factors that promote in-stent stenosis, for example, blood flow disturbance near the inner wall of the blood vessel and mechanical stimulation to the blood vessel due to the flare phenomenon due to the protrusion of the strut bending part If so, there are no special restrictions. As such a stent body, a stent body made of a cobalt alloy material disclosed in Japanese Patent Nos. 3654627 and 3605388 can be used, and the disclosure of the above patent specification is incorporated herein by reference. It is. The surface of the stent body used in the present invention is not coated with a diamond-like thin film as disclosed in Japanese Patent No. 4066440. A stent body having a predetermined shape can be formed by processing with a laser processing machine or the like and performing surface finishing by polishing.

(Stent coverage)
In the present invention, a polymer coating layer is formed on at least the outer surface, preferably both the outer surface and the inner surface of the cylindrical surface of the stent body as described above, and a drug is carried on the polymer coating layer to carry out the first treatment. 1 coating layer is formed. As a method of loading a drug on the stent surface, a dipping method in which the stent is immersed in a coating solution prepared by dissolving the drug and polymer in an appropriate solvent, and the solvent is dried by lifting, or a solution in which the drug and polymer are dissolved. A spray method in which the mist is atomized and sprayed onto the stent, and a double simultaneous spray method in which the drug and the polymer are dissolved in different solvents and sprayed onto the stent simultaneously from two nozzles. Although applicable, a method in which a coating layer of a polymer in which a drug is dispersed (including molecular dispersion) is formed on the stent surface is preferable because the release rate of the drug can be easily controlled. Especially, it is preferable that the chemical | medical agent (argatroban) is micro-dispersed in a polymer in the 1st composition which forms a 1st coating layer so that it may mention later.

(First coating layer and second coating layer)
The basic structure of the stent of the present invention includes (a) a stent body, (b) a first covering layer formed on at least the outer surface of the stent body and containing a polymer and a drug (preferably argatroban), and (c) It is comprised from the 2nd coating layer which contains less than 20 weight% of polymer alone or chemical | medical agent formed on the 1st coating layer as a weight component ratio with respect to 80 weight% of polymers. The first coating layer is loaded with a drug (argatroban) at a high concentration (maintained by molecular dispersion in the polymer or micro-dispersion in the order of nanometers or submicron order particles), and the second coating layer In addition, sustained release is provided over a long period of time by suppressing the release of the drug (argatroban). By selecting the thickness of the first coating layer, the loading state of the drug (argatroban) in the polymer in the first coating layer, the thickness of the second coating layer, the polymer composition in the second coating layer, the tissue, etc. Argatroban) release rate is controlled. For this reason, the second coating layer needs to be formed so as to substantially completely cover the first coating layer.

(First composition for forming the first coating layer)
As described above, the first covering layer is formed from the first composition containing the polymer and the drug (argatroban). The weight composition ratio of the polymer and the drug (argatroban) in the first composition is 8 to 3 for the polymer and 2 to 7 for the drug (argatroban), and the ratio of the drug (argatroban) is less than 2 The drug (argatroban) release rate from the coat layer is too small, and if it exceeds 7, the coat layer becomes brittle and it is difficult to adhere to the stent substrate. In addition to the polymer and the drug (argatroban), the first composition contains a release aid (carboxylic acid ester, monoester of glycerin, diester, preferably dimethyl tartrate, diethyl tartrate, etc.) disclosed in Patent Document 2. You may go out. In the first composition, as described above, the polymer (argatroban) can be released over a long period of time because the polymer carries the drug (argatroban) at a high concentration. Therefore, it is preferable that the first composition does not contain any drug other than the intimal thickening inhibitor (argatroban) so as not to inhibit the loading of the polymer drug (argatroban) of the first composition. In the first composition, whether the drug (argatroban) is microdispersed or molecularly dispersed in the polymer can be confirmed by the presence or absence of a crystal melting heat peak by differential thermal analysis (yes: microdispersion, no: molecular dispersion). .

(Supported state of drug (argatroban) in the first composition)
As described above, it is important that the release of the drug (argatroban) from the stent is maintained even after a predetermined period of time has elapsed after being inserted into the blood, particularly into an artery, but in the stent of the present invention, 37 The release rate of the drug (argatroban) on the first and second days from the time of immersion of the stent in phosphate buffered saline at 0 ° C. is adjusted to be 3 μg / cm ² · day or more. In order for the release rate of the drug (argatroban) to be as described above, the drug (argatroban) in the first composition is microscopic as described above rather than being dissolved or molecularly dispersed in the polymer. It is preferably dispersed (micro-dispersed in the form of particles of nanometer and submicron order). When the drug (argatroban) is dissolved in the polymer of the first composition, it is difficult to cause a necessary amount to be released within a predetermined period through the second coating layer. In the first composition, it is effective for controlling the release rate of the drug (argatroban) to keep the drug (argatroban) in a supported state so that the second coating layer has a predetermined release rate. It is.

(Polymer constituting the first composition)
In the present invention, the main objective is to continuously release a drug (argatroban) in an amount effective for stenosis suppression for a certain period of time. Therefore, in the first composition, as a matrix polymer for supporting the drug (argatroban) It is preferable to use a flexible polymer having a glass transition temperature (Tg) within the range of −100 to 50 ° C. in which the drug (Argatroban) can easily move in the polymer layer by diffusion. As such a flexible polymer, silicone rubber, urethane rubber, fluororesin, polybutyl acrylate (−54 ° C.), polybutyl methacrylate (20 ° C.), acrylic rubber, natural rubber, ethylene-vinyl acetate copolymer, styrene- Examples thereof include a butadiene block copolymer, a styrene-isoprene block copolymer, and a styrene-isobutylene block copolymer. The above-mentioned flexible polymer is non-degradable when introduced into a blood vessel, but in the present invention, when it is required to recover vascular tissue early from chronic inflammation caused by the polymer, It is preferable to coat with a degradable polymer, especially one that degrades and disappears in vivo within half a year. Specific examples of the biodegradable polymer include polylactic acid, poly (lactic acid-glycolic acid), polyglycolic acid, poly (lactic acid-ε-caprolactone), poly (glycolic acid-ε-caprolactone), poly-p-dioxanone, Examples include poly (glycolic acid-trimethylene carbonate), poly-β-hydroxybutyric acid, and the like. Among them, poly (lactic acid-glycolic acid), poly (lactic acid-ε-caprolactone), and poly (glycolic acid-ε-caprolactone) have a glass transition temperature in the range of −20 to 50 ° C. and have a biodegradation rate. It is preferably used in the present invention because it is a rate of degradation and disappearance in vivo within half a year. The molecular weight of these polymers is suitably 20,000 to 500,000 from the viewpoint of ensuring the strength of the coating layer and the coating work efficiency.

(Polymer selection and drug release rate)
In general, the drug release rate from the coat layer depends on the diffusion rate of the drug in the polymer for non-degradable polymers, but depends on the diffusion rate of the drug and the degradation rate of the polymer for biodegradable polymers. Therefore, in order to control the drug release rate, the type of polymer may be appropriately selected, and different types of polymers may be combined as necessary. Therefore, the drug release rate can be controlled by adjusting two parameters, the diffusion rate of the drug in the polymer and the degradation rate of the polymer. To increase the diffusion rate of the drug in the polymer, it is appropriate to select a rubbery polymer, and to increase the biodegradability rate, to select a copolymer having a high copolymerization ratio of glycolic acid. Is appropriate.

(Selection of biodegradable polymer and drug release rate)
When a biodegradable polymer is used as the polymer of the first composition, among the above biodegradable polymers, poly (lactic acid-glycolic acid) (copolymerization ratio = 100: 0 to 0: 100), poly (lactic acid) -Ε-caprolactone) (copolymerization ratio = 100: 0 to 25:75) is preferable in terms of safety since it has been used for the human body. Since the degradation rate of the biodegradable polymer depends on the chemical structure of the monomer constituting the polymer, the copolymerization ratio, and the molecular weight, it is preferable to adjust these parameters so as to suit the target drug release rate. In the case of poly (lactic acid-glycolic acid), increasing the ratio of glycolic acid increases the degradation rate, and the copolymer with a molar ratio of 50:50 degrades and disappears in about 3 months in vivo. With such polymers, drug release is completed within 2 months.

(Adjustment of drug release rate by addition of dissolution aid)
The first composition is composed of the polymer and the drug (argatroban) as described above. Furthermore, if necessary, the dissolution rate can be increased by blending an elution aid as the third component in the composition. Can be fast. As disclosed in Patent Document 2, elution aids that can be suitably used in the present invention are dimethyl tartrate and diethyl tartrate. These elution aids can be used alone or in combination of two. As a preferred embodiment for adjusting the drug (argatroban) release rate, dimethyl tartrate and / or diethyl tartrate may be added to the biodegradable polymer coat layer. The addition amount may be appropriately set according to the drug (argatroban) release rate, but is preferably within the range of about 5 to 60 phr of the polymer weight. When it is within this range, a good additive effect can be obtained.

(Thickness of the first coating layer)
The thickness of the coat layer per unit surface area (1 cm ² ) of the stent needs to be in the range of 1 to 25 μm from the viewpoint of releasing an appropriate amount of drug (argatroban). Usually, it is preferably in the range of 2 to 20 μm. If the coating layer including the second coating layer exceeds 20 μm, the in-stent stenosis may be increased. Therefore, it is preferable that the thickness of the first coating layer does not exceed 15 μm. Therefore, the coating liquid composition and the coating conditions are selected so that these application conditions can be satisfied. The first coating layer may be formed of a single layer, or may be formed of a plurality of layers within the above range.

(Second composition)
The second coating layer may be formed by polymer alone, as components other than the polymer, anti-intoxicated bottle drug (argatroban or the like), immunosuppressive agents (rapamycin, everolimus, biolimus A9, zotarolimus, tacrolimus, etc.), anti The composition may contain a drug such as a cancer drug (such as paclitaxel) or a cholesterol-lowering drug (such as a statin) within a range of less than 20% by weight based on 80% by weight of the polymer. In addition, elution aids such as dimethyl tartrate and diethyl tartrate, and components such as saccharides, polysaccharides, amino acids, inorganic / organic salts, and proteins such as biological components are drugs (argatroban) from the first coating layer to the second coating layer. 20% by weight because it is useful for controlling the rate of permeation through the (topcoat layer) and, in some cases, for inhibiting platelet aggregation, inhibiting thrombus formation, inhibiting smooth muscle proliferation, and promoting healing of vascular endothelium. An appropriate amount may be added within a range not exceeding.

(Polymer constituting the second coating layer)
In the present invention, the polymer alone or the second coating layer (topcoat layer) made of the second composition is coated on the first coating layer (basecoat) made of the first composition, and the drug from the first coating layer is coated. Controls release rate and imparts sustained release. As a component of the second composition, it is preferable to use a substance that can move the drug (argatroban) through the topcoat layer at an appropriate speed by diffusion. A material satisfying this condition is preferably a flexible polymer having a molecular weight of 10,000 to 500,000 and a glass transition temperature of −100 ° C. to 60 ° C. Specific examples of such polymers include silicone rubber, urethane rubber, fluororesin, polybutyl acrylate (−54 ° C.), polybutyl methacrylate (20 ° C.), acrylic rubber, natural rubber, ethylene-vinyl acetate copolymer, styrene- Nondegradable polymers such as a butadiene block copolymer, a styrene-isoprene block copolymer, and a styrene-isobutylene block copolymer are exemplified. When it is required to recover the vascular tissue early from the chronic inflammation caused by the polymer, it is preferable to use a biodegradable polymer, and more preferably one that degrades and disappears in vivo within half a year. Specific examples of the biodegradable polymer used in the present invention include polylactic acid, poly (lactic acid-glycolic acid), polyglycolic acid, poly (lactic acid-ε-caprolactone), poly (glycolic acid-ε-caprolactone), poly -P-dioxanone, poly (glycolic acid-trimethylene carbonate), poly-β-hydroxybutyric acid, etc., among others, poly (lactic acid-glycolic acid), poly (lactic acid-ε-caprolactone), poly (glycolic acid) -Ε-caprolactone) is preferably used in the present invention because it has a glass transition temperature in the range of −20 to 60 ° C. and decomposes and disappears in vivo within half a year. The molecular weight of these polymers is suitably in the range of 10,000 to 500,000 from the viewpoint of ensuring the strength of the second coating layer and the coating work efficiency. The polymer of the second coating layer and the polymer of the first coating layer may be the same or different.

(Thickness of the second coating layer)
The film thickness of the second coating layer is preferably in the range of 0.5 to 5 μm. If it is less than 0.5 μm, the uniformity of the film cannot be ensured, and the function of suppressing the drug (argatroban) release rate cannot be exhibited. Conversely, if the thickness exceeds 5 μm, there is a risk that the drug (argatroban) release rate will be too slow. The second coating layer may be a single layer or may be formed of a plurality of layers within the above range.

(Formation method of a 1st coating layer)
In order to coat the surface of the stent body with a matrix polymer carrying a drug (argatroban), a solution in which the drug and polymer are dissolved in a volatile solvent (eg, fluorinated alcohol) is sprayed on the stent surface, or the stent body Is immersed in the solution, applied to the stent body, and dried. In the present invention, the first composition containing a drug (argatroban) is coated on at least the outer surface (the surface in contact with the blood vessel wall) of the cylindrical stent body. In this case, the application is preferably performed by spraying a solution obtained by dissolving the first composition in a solvent on the outer surface of the stent body. Further, when the treatment is performed not only on the outer surface but also on the inner surface, it is preferable to spray both the inner and outer surfaces or impregnate the stent body in the solution. The removal of the solvent after coating is appropriately performed by a method such as decompression, air blowing, and heating.

(Stent treatment of the stent body)
When coating the above coating solution on the stent surface, the coating layer that remains after the solvent volatilizes needs to adhere to the stent surface, so the surface of the stent body should be washed or surface-activated as necessary before the coating operation. It is preferable to perform the conversion process. Examples of the surface treatment method include chemical treatment with an oxidizing agent and fluorine gas, surface graft polymerization, plasma discharge treatment, corona discharge treatment, UV / ozone treatment, and electron beam irradiation.

(Selection of solvent for forming the first composition)
Examples of volatile solvents having a boiling point of less than 100 ° C. that can dissolve the drug (argatroban) and can be easily removed after coating include methanol, ethanol, trifluoroethanol, hexafluoroisopropanol, and mixed solvents containing these alcohols. It is done. As the polymer, the polymers exemplified above are used. Among them, poly (lactic acid-glycolic acid) and poly (lactic acid-ε-caprolactone) having high polarity are preferable from the viewpoint of solubility in the above solvent. Solvents suitable for dissolving both the drug (argatroban) and the above-mentioned polymer and providing sustained release of the drug include trifluoroethanol and hexafluoroisopropanol, as well as lower solvents such as ethyl acetate, methyl acetate, and butyl acetate. Mixed solvent of alkyl ester (carbon number: 6 or less) and methanol, mixed solvent of lower alkyl ketone (carbon number: 6 or less) and methanol such as acetone, methyl ethyl ketone, lower halogenated hydrocarbon such as methylene chloride, chloroform, dichloroethane ( Examples thereof include a mixed solvent of carbon number: 4 or less) and methanol. Among them, from the viewpoint of giving a drug (argatroban) micro-dispersed in a polymer to give sustained drug release properties, a mixed solvent of a lower alkyl ester and methanol, a mixed solvent of a lower alkyl ketone and methanol, and a lower halogenated hydrocarbon and methanol. Mixed solvents are preferred. When the coating layer is formed using these mixed solvents and the solvent is removed, the drug (argatroban) is supported in a micro-dispersed state on the polymer, and when the second coating layer is formed thereon, the drug ( Argatroban) release rate would be desirable.

(Formation of second coating layer)
A 2nd coating layer is formed by apply | coating the solution which melt | dissolved the polymer in the solvent or the solution which melt | dissolved the 2nd composition which consists of a polymer and another structural component on a 1st coating layer. The application method is the same as the formation of the first coating layer.

(Formation of second composition)
As the solvent for forming the polymer that forms the second coating layer or the second composition containing the polymer and other components, the solvent that forms the first composition can be used, but it does not dissolve argatroban. The method of coating the polymer and other components with a solvent (lower alkyl ester, lower alkyl ketone, lower halogenated hydrocarbon, etc.) that dissolves is preferable in that the drug release rate can be precisely controlled. In this case, the second composition does not contain argatroban.

(Adjustment of drug release rate)
In order for the drug sustained-release stent of the present invention to remarkably suppress in-stent stenosis, as is apparent from the animal test results described in the Examples (including Reference Examples) section, the phosphate buffered physiology at 37 ° C. Argatroban is 3 μg / cm ² · day or more, preferably 4 μg / cm ² · day or more, more preferably 6 μg / cm ² · day or more for at least 2 days after immersing the stent in saline (pH 7.4). The inventor has found that the release rate needs to be adjusted to release at a rate. The upper limit of the release rate is not necessarily clear from the viewpoint of the effect of suppressing stenosis, but if the amount of the drug is too large, there is a risk of causing side effects such as bleeding, and the use of an excessive amount of the drug is a point of manufacturing cost. Therefore, 500 μg / cm ² · day, usually 300 μg / cm ² · day is appropriate. The release rate after the third day is not an essential condition for suppressing in-stent stenosis, but since continuous argatroban release after the third day is expected to further enhance the stenosis-inhibiting effect, 2 μg / It is desirable that the drug release rate of cm ² · day or more continues for 1-2 weeks after the third day. The drug-coated layer according to the present invention is particularly preferred as a method for releasing the argatroban at a rate of 3 μg / cm ² · day or more for the first at least two days after the stent is placed in the artery. That is, a first composition comprising 20 to 70% by weight of argatroban and 80 to 30% by weight of polymer is uniformly coated on the outer surface of the cylindrical stent body within a thickness range of 1 to 15 μm, and The polymer alone or the polymer and the drug are included so as to substantially completely cover the surface of the first coating layer formed from the first composition, and the weight composition ratio of the drug with respect to 80% by weight of the polymer is less than 20% by weight. For stents that are uniformly coated with a second coating layer comprising the second composition, the release rate of argatroban is at least 2 days after immersing the stent in 37 ° C. phosphate buffered saline (pH 7.4). during the argatroban 3 [mu] g / cm ² · day or more, preferably 4 [mu] g / cm ² · day or more, more preferably released at 6 [mu] g / cm ² · day or faster It can be realized by adjusting the so that the release rate.

  The release rate of the drug (argatroban) is such that the drug (argatroban) is supported at a high concentration in the polymer of the first composition, and the second coating layer contains the polymer alone or the drug in a small amount of less than 20% by weight. When the dense polymer layer formed from the product is present in a thickness range of 0.5 to 5 μm, the release of the drug (argatroban) contained in the first coating layer is suppressed, thereby providing sustained release. In particular, in the first coating layer, it is preferable that the drug (argatroban) is supported on the polymer in a microdispersed state. In order to support the drug (argatroban) in a microdispersed state, it is possible to select the solvent used when preparing the composition containing the polymer and the drug (argatroban) as described above.

The release rate of the drug (argatroban) is affected by the polymer constituting the first composition and the second coating layer, but can be controlled by changing the thickness of the coating layer within the above range depending on the polymer used. . Of these, a copolymer of lactic acid and glycolic acid is preferable.
(Example)

  EXAMPLES Hereinafter, the present invention will be specifically described by way of examples. However, these examples are not intended to limit the present invention. The materials used in the examples, the amount used, the concentration, the numerical conditions such as the processing temperature, the processing method and the like are only suitable examples within the scope of the present invention.

[Production Example 1]
A uniform solution (coating solution) was prepared by dissolving 140 mg of argatroban and 160 mg of poly D, L-lactic acid / glycolic acid copolymer (molar ratio: 50/50) in 20 mL of 2,2,2-trifluoroethanol. 1 is a mandrel of a spray-type coating device having a stent body (referred to as Stent1) having an outer diameter of 1.55 mmΦ, a post-expansion inner diameter = 3 mmΦ, a length of 17 mm, and a total surface area = 0.70 cm ² having the design shown in FIG. Attached to. The coating liquid is sprayed from the nozzle at a speed of 20 μL / min, and the stent body is reciprocated while rotating at a speed of 120 revolutions per minute at a position 9 mm below the nozzle, and from the end to the center of the stent body for about 4 minutes. The surface was coated. The stent was dried under nitrogen flow for 10 minutes after the coating was completed, and then the other half was coated. The stent having been fully coated was air-dried for about 1 hour and then dried at 60 ° C. for 17 hours in a vacuum thermostatic dryer to completely remove the solvent. 30 stent bodies were coated under the same conditions. When weighed to the unit of μg with a precision balance, the obtained stent was coated with an average of 619 μg of the mixture of argatroban and the copolymer (average first coating layer thickness 7.4 μm). Hereinafter, this stent is referred to as DES1.

[Production Example 2]
300 mg of poly D, L-lactic acid / glycolic acid copolymer (molar ratio: 50/50) was dissolved in 20 mL of chloroform to prepare a uniform solution (coating solution). DES1 produced in Production Example 1 was attached to a mandrel of a spray type coating apparatus. The coating solution is sprayed from the nozzle at a speed of 20 μL / min, and the stent is reciprocated while rotating at a speed of 120 revolutions per minute at a position of 9 mm below the nozzle to reach the surface from the end to the center of the stent for about 100 seconds. Coating was performed. The stent was dried under nitrogen flow for 10 minutes after the coating was completed, and then the other half was coated. The stent having been fully coated was air-dried for about 1 hour and then dried at 60 ° C. for 17 hours in a vacuum thermostatic dryer to completely remove the solvent. 15 stents were coated under the same conditions. The stent obtained by weighing with a precision balance was coated with an average of 103 μg of the copolymer (average thickness of the second coating layer: 1.2 μm). Hereinafter, this two-layer-coated stent (total coating amount of 722 μg, average coating layer thickness of 8.6 μm) is referred to as DES2.

[Production Example 3]
120 mg of argatroban and 180 mg of poly D, L-lactic acid / glycolic acid copolymer (molar ratio: 50/50) were dissolved in 20 mL of 2,2,2-trifluoroethanol to prepare a uniform solution (coating solution). The Stent 1 was mounted on a mandrel of a spray type coating apparatus. The coating liquid is sprayed from the nozzle at a speed of 20 μL / min, and the stent body is reciprocated while rotating at a speed of 120 revolutions per minute at a position 9 mm below the nozzle, and from the end to the center of the stent body for about 4 minutes. The surface was coated. The stent was dried under nitrogen flow for 10 minutes after the coating was completed, and then the other half was coated. The stent having been fully coated was air-dried for about 1 hour and then dried at 60 ° C. for 17 hours in a vacuum thermostatic dryer to completely remove the solvent. 30 stent bodies were coated under the same conditions. When weighed to the unit of μg with a precision balance, the resulting stent was coated with an average of 493 μg of a mixture of argatroban and the copolymer (average first coating layer thickness 5.9 μm). Hereinafter, this stent is referred to as DES3.

[Production Example 4]
300 mg of poly D, L-lactic acid / glycolic acid copolymer (molar ratio: 50/50) was dissolved in 20 mL of chloroform to prepare a uniform solution (coating solution). DES3 was mounted on a mandrel of a spray coating apparatus. The coating solution is sprayed from the nozzle at a speed of 20 μL / min, and the stent is reciprocated while rotating at a speed of 120 revolutions per minute at a position of 9 mm below the nozzle to reach the surface from the end to the center of the stent for about 100 seconds. Coating was performed. The stent was dried under nitrogen flow for 10 minutes after the coating was completed, and then the other half was coated. The stent having been fully coated was air-dried for about 1 hour and then dried at 60 ° C. for 17 hours in a vacuum thermostatic dryer to completely remove the solvent. 15 stents were coated under the same conditions. The stent obtained by weighing with a precision balance was coated with an average of 148 μg of the copolymer (average thickness of the second coating layer: 1.8 μm). Hereinafter, this bilayer-coated stent (total coating amount 641 μg, average coating layer thickness 7.6 μm) is referred to as DES4.

[Production Example 5]
120 mg of argatroban and 180 mg of poly-D, L-lactic acid were dissolved in 20 mL of an acetone / methanol mixed solvent (volume ratio: 7: 3) to prepare a uniform solution (coating solution). The Stent 1 was mounted on a mandrel of a spray type coating apparatus. The coating liquid is sprayed from the nozzle at a speed of 20 μL / min, and the stent body is reciprocated while rotating at a speed of 120 revolutions per minute at a position 9 mm below the nozzle, and from the end to the center of the stent body for about 4 minutes. The surface was coated. The stent was dried under nitrogen flow for 10 minutes after the coating was completed, and then the other half was coated. The stent having been fully coated was air-dried for about 1 hour and then dried at 60 ° C. for 17 hours in a vacuum thermostatic dryer to completely remove the solvent. 30 stents were coated under the same conditions. When weighed to the microgram unit with a precision balance, the resulting stent was coated with an average of 583 micrograms of a mixture of argatroban and the copolymer. Hereinafter, this stent (average first coating layer thickness 6.9 μm) is referred to as DES5.

[Production Example 6]
300 mg of poly D, L-lactic acid / glycolic acid copolymer (molar ratio: 50/50) was dissolved in 20 mL of ethyl acetate to prepare a uniform solution (coating solution). DES5 was mounted on a mandrel of a spray coating apparatus. The coating solution is sprayed from the nozzle at a speed of 20 μL / min, and the stent is reciprocated while rotating at a speed of 120 revolutions per minute at a position of 9 mm below the nozzle to reach the surface from the end to the center of the stent for about 100 seconds. Coating was performed. The stent was dried under nitrogen flow for 10 minutes after the coating was completed, and then the other half was coated. The stent having been fully coated was air-dried for about 1 hour and then dried at 60 ° C. for 17 hours in a vacuum thermostatic dryer to completely remove the solvent. 15 stents were coated under the same conditions. When weighed to the unit of μg with a precision balance, the obtained stent was coated with an average of 255 μg of the copolymer mixture (average second film thickness of 3.0 μm). Hereinafter, this two-layer coated stent (total coating amount 838 μg, average covering layer thickness 10.0 μm) is referred to as DES6.

[Production Example 7]
300 mg of poly D, L-lactic acid / glycolic acid copolymer (molar ratio: 50/50) was dissolved in 20 mL of 2,2,2-trifluoroethanol to prepare a uniform solution (coating solution). Stent 1 was mounted on a mandrel of a spray coating apparatus. The coating liquid is sprayed from the nozzle at a speed of 20 μL / min, and the stent body is reciprocated while rotating at a speed of 120 revolutions per minute at a position 9 mm below the nozzle, and from the end to the center of the stent body for about 4 minutes. The surface was coated. The stent was dried under nitrogen flow for 10 minutes after the coating was completed, and then the other half was coated. The stent having been fully coated was air-dried for about 1 hour and then dried at 60 ° C. for 17 hours in a vacuum thermostatic dryer to completely remove the solvent. Ten stents were coated under the same conditions. When weighed to the microgram unit with a precision balance, the resulting stent was coated with an average of 487 micrograms of the copolymer. Hereinafter, this stent (average covering layer thickness 5.8 μm) is referred to as PCS1.

<Drug release test 1>
The drug release rates from the six types of drug-coated stents shown in Production Examples 1 to 6 were measured. Each stent was mounted on a balloon catheter having a diameter of 3 mm and a length of 20 mm, and sterilized with ethylene oxide gas (EOG). After sterilization, the balloon catheter was pressurized at about 12 atmospheres for 30 seconds, and the stent was expanded to a diameter of 3 mm. Three stents were placed in a clean sealed glass container and 30 mL of pH 7.4 phosphate buffered saline was added. The whole stent was immersed in the liquid and shaken in a 37 ° C. incubator.

The UV absorption (331 nm) of the eluate was measured with a UV-visible spectrophotometer UV-2450 (manufactured by Shimadzu) every predetermined time, and the absorbance of argatroban was measured. A calibration curve was prepared using phosphate buffered saline with a concentration of 0.001% and 0.0001% of argatroban, and the absorbance was converted into a concentration, and the amount of argatroban released per cm ^{2 of the} eluted stent surface area was determined. The results are shown in Table 1.

From Table 1, the drug-coated stents coated with two layers (DES2, DES4, and DES6) did not show any burst-like rapid release within 24 hours of immersion, and the release of argatroban between 24 and 48 hours of immersion. The amount was 4 μg / cm ² · day or more, indicating the release of argatroban.

<Animal test 1>
Drug releasing stents prepared in Production Example 1, 2, 4, 6, PCS1 subjected only polymer coating DES1,2,4,6 and preparations 7, S t 6 types of stents each six ent1, total 36 The book was implanted in 18 coronary arteries (LAD, LCX) of crown minipigs (weight 25-40 kg), and the degree of in-stent stenosis was evaluated by quantitative coronary angiography (QCA) after 1 month.

  Each stent was mounted on a balloon catheter and EOG sterilization was performed. Each stent was inserted into the coronary artery using a 6Fr guiding catheter from the right femoral artery of a minipig under general anesthesia using a sheath introducer. Select the implantation site and the stent expansion pressure so that the vessel diameter (proximal part) after stent implantation is within the range of 1.0 to 1.2 relative to the original vessel diameter. I planted. Aspirin 100 mg and clopidogrel 50 mg were mixed and administered for 33 days from 3 days before implantation to stent extraction.

30 days after implantation, the diameter of the blood vessel lumen at the stent implantation site was measured at three locations, the proximal portion, the central portion, and the distal portion of the stent. The stenosis rate was calculated by the following formula.
Vessel diameter stenosis rate = (lumen diameter immediately after implantation-lumen diameter after one month) / lumen diameter immediately after implantation x 100
Table 2 shows the calculated average vessel diameter stenosis rate (%).

As can be seen from Table 2, the stenosis rate is smaller in DES4 (Example 2) where the amount of drug released during 24 to 48 hours is 4 μg / cm ² · day or more than in Stent1 (Comparative Example 3). On the other hand, DES1 (Comparative Example 1) of 1 μg / cm ² · day or less shows almost the same stenosis rate as PCS1 (Comparative Example 2) containing no drug, and no stenosis-inhibiting effect is observed at all. The stenosis rate is larger than Stent 1 (Comparative Example 3) of the stent, and only an adverse effect due to the polymer coating appears.

<Animal test 2>
Six stents (DES2) produced in Production Example 2 and six stents (DES5) produced in Production Example 5 (Comparative Example 4) were made into six coronary arteries (LAD, LCX) 12 in a crown-type minipig (weight 25-36 kg). The book was implanted according to the procedure of animal test 1, and the heart excised after 28 days of pathological dissection was fixed with formalin. The blood vessel tissue in which the stent was implanted was cut out from the heart, fixed with acrylic resin, and then cut at three locations at the center and both ends of the stent to prepare a thin section having a thickness of 6 μm. These were stained with hematoxylin and eosin staining and elastica-Wangeson staining, and the area stenosis rate (%) and the endothelial cell coverage rate (%) were evaluated. In DES2, the area stenosis rate was 28 ± 8%, which almost coincided with the average vessel diameter stenosis rate in Example 1. Endothelial cell coverage was 100%, and damage to the inner wall of the blood vessel at the time of stent implantation was completely healed. In DES5, the area stenosis rate was 64 ± 16%, which almost coincided with the average blood vessel diameter stenosis rate of Comparative Example 1 and Comparative Example 2. For comparison, an example of a pathological specimen of DES2 is shown in FIG. 2, and an example of a pathological specimen of DES5 is shown in FIG.

Argatroban supported on the surface of the arterial stent is in a phosphate buffered saline (pH 7.4) at 37 ° C. at a rate of ^{3 to} 300 μg / cm ² · day for at least 2 days from the time of immersion of the stent. A drug sustained-release arterial stent was created in which the release rate of argatroban was controlled to be released. When this is placed in the artery, the released argatroban can effectively suppress intimal thickening, and the inner wall of the blood vessel is almost completely covered with endothelial cells within one month of stent placement. And from the results of animal experiments.

[Reference Production Example 1]
Dissolve 140 mg of argatroban and 160 mg of poly D, L-lactic acid / glycolic acid copolymer (molar ratio: 65/35) in 20 mL of an acetone / methanol mixed solvent (volume ratio = 7: 3) to obtain a uniform solution (coating solution). Prepared. A cobalt alloy stent having the same shape as the Stent 1 and coated with a diamond-like thin film was plasma-discharge treated, and then mounted on a mandrel of a spray coating apparatus. The coating liquid is sprayed from the nozzle at a speed of 20 μL / min, and the stent body is reciprocated while rotating at a speed of 120 revolutions per minute at a position 9 mm below the nozzle, and from the end to the center of the stent body for about 4 minutes. The surface was coated. The stent was dried under nitrogen flow for 10 minutes after the coating was completed, and then the other half was coated. The stent having been fully coated was air-dried for about 1 hour and then dried at 60 ° C. for 17 hours in a vacuum thermostatic dryer to completely remove the solvent. Ten stent bodies were coated under the same conditions. When weighed to the unit of μg with a precision balance, the resulting stent was coated with an average of 643 μg of the mixture of argatroban and the copolymer (average first coating layer thickness 7.7 μm). Hereinafter, this stent is referred to as DES7.

[Reference Production Example 2]
150 mg of poly D, L-lactic acid / glycolic acid copolymer (molar ratio: 65/35) was dissolved in 20 mL of the acetone-methanol mixed solvent to prepare a uniform solution (coating solution). DES7 produced in Production Example 8 was attached to a mandrel of a spray type coating apparatus. The coating liquid is sprayed from the nozzle at a speed of 20 μL / min, and the stent is reciprocated while rotating at a speed of 120 revolutions per minute at a position 9 mm below the nozzle to reach the surface from the end to the center of the stent for about 180 seconds. Coating was performed. The stent was dried under nitrogen flow for 10 minutes after the coating was completed, and then the other half was coated. The stent having been fully coated was air-dried for about 1 hour and then dried at 60 ° C. for 17 hours in a vacuum thermostatic dryer to completely remove the solvent. Ten stents were coated under the same conditions. The stent obtained by weighing with a precision balance was coated with an average of 241 μg of the copolymer (thickness: 2.9 μm). Hereinafter, this two-layer-coated stent (total coating amount 884 μg, average covering layer thickness 10.5 μm) is referred to as DES8.

[Reference Example]
<Reference drug release test>
The drug release rate from the drug-coated stent shown in Reference Production Example 2 was measured. Each stent was mounted on a balloon catheter having a diameter of 3 mm and a length of 20 mm, and sterilized with ethylene oxide gas (EOG). After sterilization, the balloon catheter was pressurized at about 12 atmospheres for 30 seconds, and the stent was expanded to a diameter of 3 mm. Three stents were placed in a clean sealed glass container and 30 mL of phosphate buffered saline at pH 7.4 was added. The whole stent was immersed in the liquid and shaken in a 37 ° C. incubator.

The UV absorption (331 nm) of the eluate was measured with a UV-visible spectrophotometer UV-2450 (manufactured by Shimadzu) every predetermined time, and the absorbance of argatroban was measured. A calibration curve was prepared using phosphate buffered saline of 0.001% and 0.0001% argatroban, and the absorbance was converted into a concentration, and the amount of argatroban released per 1 cm ² of the released stent surface area was determined. The results are shown in Table 3.

From Table 3, in the two-layer coated drug-coated stent (DES8), no burst-like rapid release within 24 hours of immersion was observed, and the release amount of argatroban was 46 μg during 24 to 48 hours of immersion. / Cm ² · day or more, indicating release of argatroban.

[Examples 4 to 7]
30 mg of argatroban and 90 mg of poly D, L-lactic acid / glycolic acid copolymer (molar ratio: 65/35) were dissolved in 5 mL of four organic solvents shown in Table 4 and cast onto a glass plate. This was air-dried at room temperature for 6 hours and then vacuum-dried at 60 ° C. for 17 hours to recover a polymer film containing argatroban. This film was thermally analyzed by a DSC apparatus (differential scanning calorimetry). The temperature was raised from room temperature to 210 ° C. at a rate of 5 ° C. per minute, and the crystal melting temperature (endothermic peak temperature) of argatroban was measured. The results are shown in Table 4. In the coating using 2,2,2, -trifluoroethanol, no endothermic peak appeared between room temperature and 210 ° C., and it was assumed that argatroban was molecularly dispersed in the polymer. On the other hand, when an acetone-methanol mixed solvent, an ethyl acetate-methanol mixed solvent, and a 1,2, dichloroethane-methanol mixed solvent were used, an endothermic peak due to crystal melting of argatroban appeared around 178 ° C. From this, it was found that there was a difference in the dispersion state of argatroban incorporated into the polymer depending on the solvent used.

The cast film was cut into 3 cm ² pieces on the surface and 30 mL of phosphate buffered saline at pH 7.4 was added. The whole stent was immersed in the liquid and shaken in a 37 ° C. incubator. The UV absorption (331 nm) of the eluate from the 2nd day to the 7th day after the start of immersion was measured with an ultraviolet-visible spectrophotometer UV-2450 (manufactured by Shimadzu), and the absorbance of argatroban was measured. A calibration curve was prepared using phosphate buffered saline of 0.001% and 0.0001% argatroban, and the absorbance was converted into a concentration, and the amount of argatroban released per 1 cm ² of the released stent surface area was determined. The results are shown in Table 4. Compared to Example 4 where no endothermic peak appeared, the amount of argatroban released in Examples 5, 6 and 7 where an endothermic peak appeared was 10 times or more.

<Reference animal test>
Ten stents (DES8) produced in Reference Production Example 2 and ten commercially available drug release stents “Cyper” (Johnson & Johnson Co., Ltd.) using rapamycin (immunosuppressive agent) as an intimal thickening inhibitor Were implanted into 20 coronary arteries (LAD, LCX, RCA) of 20 crown minipigs (weight 27-43 kg) according to the procedure of animal test 1, and the heart excised by pathological dissection 90 days later was fixed with formalin. The blood vessel tissue in which the stent was implanted was cut out from the heart, fixed with acrylic resin, and then cut at three locations at the center and both ends of the stent to prepare a thin section having a thickness of 6 μm. These were stained with hematoxylin and eosin staining and elastica-Wangeson staining, and the area stenosis rate (%) and the endothelial cell coverage rate (%) were evaluated. In DES8, the area stenosis rate was 30 ± 13%, the endothelial cell coverage was 100%, and the damage to the inner wall of the blood vessel at the time of stent implantation was completely healed. In Cypher, the area stenosis rate was 54 ± 22%, and the endothelial cell coverage was 95%.

  In the drug sustained-release stent of the present invention, the vascular endothelium was completely repaired one month after the stent was implanted in the minipig, but in Cypher, a part of the inner wall of the blood vessel was covered with endothelial cells even after 3 months. Was not.

  Although specific embodiments of the present invention have been described, it is clear that those skilled in the art can readily modify the above-described embodiments described herein. Therefore, the present invention is not limited to the specific embodiments shown in this specification, but can be applied to any other modifications, changes, and utilizations of the embodiments. All modifications, changes and embodiments should be considered as falling within the spirit and scope of the invention.

Related applications

  This application claims the priority of Japanese Patent Application No. 2007-228788, filed on Sep. 4, 2007, which is incorporated by reference in its entirety as a part of this application.

  The present invention relates to a sustained drug release stent useful for treatment of a stenotic vasculature, a method for producing the stent, and a method for adjusting the release rate of the drug from the stent. More specifically, the present invention relates to a stent loaded with an intimal thickening inhibitor that does not inhibit endothelial cell proliferation, a method for producing the stent, and a method for adjusting a drug release rate from the stent.

  A stent treatment method that mechanically dilates an arterial lesion that has been narrowed due to the progress of arteriosclerosis with a balloon catheter and restores blood flow by placing a metal stent in the lumen of the artery is rapidly spreading in recent years. It has become. In coronary arteries, which are likely to be life-threatening due to stenosis / occlusion, even if a stent is placed, the intima of the blood vessel will soon thicken, and the lumen secured by the placement of the stent will be narrowed, requiring retreatment. Probability reaches 20-30%. Therefore, in order to suppress stenosis in the stent, an attempt is made to suppress the stenosis by carrying a drug that can be expected to have a stenosis suppressing effect on the stent surface and gradually releasing the drug in the blood vessel, and sirolimus (immunosuppressant) and paclitaxel ( This led to the practical application of a drug release stent (hereinafter sometimes referred to as DES) using an anticancer agent. However, since these drugs act on the cell cycle of vascular cells (endothelial cells, smooth muscle cells) to stop proliferation, they only suppress intimal thickening due to excessive proliferation of smooth muscle cells. In addition to this, the proliferation of endothelial cells detached at the time of stent placement is also suppressed, and the side effect of delaying repair / healing of the blood vessel inner wall occurs. Since blood clots are likely to occur in areas where the inner wall of the blood vessel is not covered with endothelial cells, antithrombotic agents must be taken for a long period of more than half a year, and even if antithrombotic agents are taken, delayed thrombus There is a risk of dysfunction and sudden death.

The first event in the causal relationship from in-stent placement to in-stent stenosis is “injury to blood vessels during stent placement, especially to endothelial cells”, followed by “thrombosis” at the injury site. It is said that a causal relationship is established in the order of “generation”, “adhesion / infiltration of leukocytes into blood vessels”, “inflammation”, “smooth muscle cell proliferation”, and “stenosis”. Therefore, based on the speculation that suppressing thrombus formation is an effective measure for suppressing stenosis, the application of antithrombotic drugs such as heparin and hirudin to drug-releasing stents has been energetically studied in the early stages of development. However, clinical efficacy was not confirmed. As drug-releasing stents using sirolimus paclitaxel have become popular, antithrombotic-coated stents are a minority. Currently, stents drug carrying intimal hyperplasia inhibitor which does not inhibit proliferation of endothelial cells sustained release has not been put into practical use.
On the other hand, Patent Document 1 describes a stent that releases both drugs of argatroban (anticoagulant) and cilostazol (antiplatelet agent). Patent Document 2 describes a drug release rate from a polymer film containing argatroban soaked in a phosphate buffer solution (pH 7.4) for 3 weeks. However, the remarkable intimal thickening suppression effect in the state carried by the stent has not yet been found.

JP 2001-190687 A WO2007 / 058190

  An object of the present invention is to provide a stent that can carry an intimal thickening inhibitor that does not inhibit endothelial cell proliferation and that can gradually release the agent, and a method for producing the stent.

  Another object of the present invention is to provide a method for adjusting the release rate of a drug from a stent.

A first configuration of the present invention is formed in a cylindrical shape having an outer surface and an inner surface, and the surface of the stent body is not coated with a diamond-like thin film, and covers at least the outer surface of the stent body. A first coating layer, and a second coating layer covering the first coating layer substantially completely, wherein the first coating layer comprises a polymer , Ximelagatran A vascular intima suppressant that does not inhibit endothelial cell proliferation , selected from the group consisting of Melagatran, Melagatran, Dabigatran, and Dabigatran etexilate , The thickness composition ratio of the thickening inhibitor is formed by the first composition in the range of the polymer 8 to 3 to the intima thickening agent 2 to 7, and the second coating layer is formed of the polymer alone. A stent formed by itself or formed from a second composition comprising a polymer and a drug, wherein the drug has a weight composition of less than 20% by weight based on 80% by weight of the polymer.

  In the above-mentioned present invention, the term “stent” means that when a blood vessel or other in-vivo lumen is stenotic or occluded, the stenotic part or the like is expanded to secure a necessary lumen region. This is a tubular medical device to be placed. The stent is inserted into the body with a small diameter and is used to expand the stenosis part to increase the diameter and to hold the lumen part in an expanded state.

  In the present invention, the term “polymer” is used as a term including a homopolymer, a copolymer, or a mixture of polymers.

  In the present invention, the “first composition” and the “second composition” include a polymer and a drug, and the drug is dispersed in a polymer structure (including a dense tissue or a porous tissue) or in a fine solid state. It is what is micro-dispersed. As will be described later, in the first composition, the drug (argatroban) is preferably microdispersed in the polymer structure, and in the second composition, the polymer structure is preferably a dense structure. In the present invention, the “dense tissue” refers to a tissue in which almost no voids are observed in the tissue by observation with an optical microscope.

In the present invention, the vascular intimal hyperplasia inhibitor which does not inhibit proliferation of endothelial cells, the above ximelagatran (ximelagatran), melagatran (Melagatran), dabigatran (dabigatran), but dabigatran-Etekireto (dabigatran etexilate) and the like, the Since the inventors have made specific studies on argatroban, which is a similar suppressor for intimal thickening, hereinafter, argatroban will be described as an example.

In the present invention, “argatroban” is (2R, 4R) -4-methyl-1- [N ² -((RS) -3-methyl-1,2,3,4) represented by the following chemical structural formula. -Tetrahydro-8-quinolinesulfonyl) -L-arginyl] -2-piperidinecarboxylic acid, hydrate. Argatroban is already known as a compound having an antithrombin action (Patent Documents 1 and 2).

  In the first configuration of the present invention, the thickness of the first coating layer is in the range of 1 to 20 μm, and the thickness of the second coating layer is in the range of 0.5 to 5 μm. preferable.

It is preferable that the intimal thickening inhibitor (argatroban) in the first coating layer is microdispersed in the polymer.

It is preferable that the first coating layer does not contain a drug other than the intimal thickening inhibitor (argatroban) .

  The second coating layer is preferably formed from a polymer alone.

  When the second coating layer is formed from the second composition, the drug of the second composition is preferably argatroban, rapamycin, everolimus, biolimus A9, zotarolimus, tacrolimus, paclitaxel or statin.

  The polymer that forms the first composition and / or the second coating layer is preferably a biodegradable polymer.

  The biodegradable polymer is preferably polylactic acid, poly (lactic acid-glycolic acid), polyglycolic acid, poly (lactic acid-ε-caprolactone), or poly (glycolic acid-ε-caprolactone).

  It is preferable that the stent body is formed of a metal material, a ceramic, or a polymer material. In the present invention, the surface of the stent body is not coated with a diamond-like thin film.

  According to a second configuration of the present invention, a stent is prepared by using a solution obtained by dissolving the first composition in a lower alkyl ketone-methanol mixed solvent, a lower alkyl ester-methanol mixed solvent, or a lower halogenated hydrocarbon-methanol mixed solvent. In this stent manufacturing method, at least the outer surface of the main body is coated, and after the coating, the solvent is removed to form the first coating layer.

According to a third configuration of the present invention, in the stent according to the first configuration of the present invention, a thickness of the second coating layer is selected within a range of 0.5 to 5.0 μm. By adjusting the release rate of argatroban on the first day and the second day from the time of immersion of the stent in a phosphate buffered saline solution at 37 ° C. to be 3 μg / cm ² · day or more, respectively. A method for adjusting the release rate of argatroban from a stent.

In the stent according to the first configuration of the present invention described above, the second covering layer has a thickness of 37 ° C. by selecting a predetermined thickness within a range of 0.5 to 5.0 μm. In physiological saline, it is preferable that the release rate of the intimal thickening inhibitor (argatroban) on the second day from the time of immersion of the stent is in the range of 3 to 100 μg / cm ² · day.

In the stent according to the first configuration of the present invention described above, the second covering layer has a thickness of 37 ° C. by selecting a predetermined thickness within a range of 0.5 to 5.0 μm. In physiological saline, the release rate of the intima thickening inhibitor (argatroban) from the 3rd day to the 7th day from the time of immersion of the stent is adjusted so as to be in the range of ^{2 to} 50 μg / cm ² · day. Is preferred.

In the first composition, it is preferable that the release rate of the vascular intimal thickening inhibitor (argatroban ) is adjusted by microdispersing the vascular intimal thickening inhibitor (argatroban) in the polymer.

  The solvent for dissolving the first composition is selected from a lower alkyl ester-methanol mixed solvent, a lower alkyl ketone-methanol mixed solvent, or a lower halogenated hydrocarbon-methanol mixed solvent, and the first solvent is selected according to the selected solvent. It is preferable that the release rate of argatroban is adjusted by coating the surface of the stent body using a solution in which the composition is dissolved, and then removing the solvent to form the first coating layer after coating.

The polymer of the second coating layer is a poly (lactic acid-glycolic acid) copolymer, and by changing the copolymerization ratio of lactic acid and glycolic acid, the release rate of the intimal thickening inhibitor (argatroban) is adjusted. It is preferable.

According to a fourth configuration of the present invention, the stent of the first configuration of the present invention is placed in a blood vessel, and an intimal thickening inhibitor (argatroban) is released from the stent to inhibit the proliferation of endothelial cells. This is a method for suppressing intimal thickening without vascular injury.

  According to the first configuration of the present invention, the first coating layer is composed of an intimal thickening inhibitor (preferably argatroban) that does not inhibit the proliferation of endothelial cells and a polymer, and the weight composition ratio thereof is polymer 8-3. The anti-intimal thickening inhibitor is in the range of 2 to 7, and the first covering layer contains a large amount of the intimal thickening inhibitor, and the second covering layer is formed of the polymer alone, or , The second composition comprising a polymer and a drug, wherein the weight ratio of the drug to 80% by weight of the polymer is less than 20% by weight. Since it can be released, it is possible to obtain a stent that can exert the effect of suppressing the intimal thickening without inhibiting the proliferation of endothelial cells. In particular, the second coating layer does not contain or contains a small amount of a drug. In particular, when the second coating layer does not contain a drug, the polymer structure constituting the second coating layer has a high density. Since it is maintained, the release of the drug (argatroban) contained in the first coating layer is suppressed, and the effect of sustained release is great.

  Furthermore, according to the stent of the first configuration of the present invention, the first coating layer has a thickness in the range of 1 to 20 μm, the second coating layer has a thickness in the range of 0.5 to 5 μm, and both layers are combined. However, a thickness of 25 μm or less, preferably 20 μm or less is particularly desirable for preventing stenosis.

  In the second configuration of the present invention, the lower alkyl ketone, lower alkyl ester or lower halogenated hydrocarbon used as the solvent for dissolving the first composition is a solvent for dissolving the polymer, and methanol is a drug (argatroban). It is a solvent that dissolves. By using the mixed solvent, both the polymer and the drug (argatroban) can be dissolved. In the first coating layer formed from the polymer / drug (argatroban) composition formed using this mixed solvent, (Argatroban) is not dissolved (molecularly dispersed) in the polymer of the coating layer, but is micro-dispersed, so that the drug release rate can be easily controlled by controlling the thickness of the second coating layer, etc. Have.

  According to the third configuration of the present invention, in the stent of the first configuration of the present invention, in particular, the first coating containing a high concentration of argatroban (preferably argatroban is microdispersed in the polymer of the first coating layer). By controlling the thickness of the second coating layer formed on the layer to an appropriate thickness within the range of 0.1 to 5 μm, the release rate of argatroban can be adjusted to be within the above range. it can. This makes it possible to obtain a desired release rate.

According to the third configuration of the present invention, argatroban in the covering layer formed on the stent body has a rate of 3 μg / cm ² · day or more over at least 2 days after the stent is placed in a blood vessel, particularly in an artery. Released at. As a result, the pharmacological effect (suppression of intimal thickening) of the released argatroban appears, and the stenosis in the stent is effectively suppressed. Furthermore, one month after the placement of the stent, the endothelial cells cover the entire intimal surface, and as a result, the occurrence of thrombosis, particularly late thrombosis, is reduced compared to existing drug-releasing stents. Has a remarkable effect.

  The drug sustained-release stent of the present invention is effectively used for stent treatment of coronary arteries, but is also effective for stent treatment of cerebral artery, renal artery, and peripheral artery.

The present invention will be clearly understood from the following description of preferred embodiments with reference to the accompanying drawings. However, the embodiments and drawings are merely for illustration and description and should not be used to define the scope of the present invention. The scope of the invention is defined by the appended claims.
It is a perspective view which shows one example of the shape of the stent main body used in this invention. It is a figure which shows the pathological sample of the blood vessel cross section of DES2. It is a figure which shows the pathological sample of the blood vessel cross section of DES5.

(Stent)
The material constituting the stent body is not particularly limited, and conventionally known metal materials, ceramics, and polymer materials are used. Among them, a metal having high rigidity and corrosion resistance is preferable. Specific examples include stainless steel, tantalum, nickel-titanium alloy (including nitinol), magnesium alloy, and cobalt alloy (including cobalt-chromium-nickel alloy). The stent body has a cylindrical shape having an outer surface and an inner surface, and may be a balloon expandable type, a self-expandable type, or a combination thereof. FIG. 1 is a perspective view showing an example of the shape of a stent body used in the present invention, particularly as a drug releasing stent. As for the mesh design of the stent body and the shape of the struts, the factors that promote in-stent stenosis, for example, blood flow disturbance near the inner wall of the blood vessel and mechanical stimulation to the blood vessel due to the flare phenomenon due to the protrusion of the strut bending part If so, there are no special restrictions. As such a stent body, a stent body made of a cobalt alloy material disclosed in Japanese Patent Nos. 3654627 and 3605388 can be used, and the disclosure of the above patent specification is incorporated herein by reference. It is. The surface of the stent body used in the present invention is not coated with a diamond-like thin film as disclosed in Japanese Patent No. 4066440. A stent body having a predetermined shape can be formed by processing with a laser processing machine or the like and performing surface finishing by polishing.

(Stent coverage)
In the present invention, a polymer coating layer is formed on at least the outer surface, preferably both the outer surface and the inner surface of the cylindrical surface of the stent body as described above, and a drug is carried on the polymer coating layer to carry out the first treatment. 1 coating layer is formed. As a method of loading a drug on the stent surface, a dipping method in which the stent is immersed in a coating solution prepared by dissolving the drug and polymer in an appropriate solvent, and the solvent is dried by lifting, or a solution in which the drug and polymer are dissolved. A spray method in which the mist is atomized and sprayed onto the stent, and a double simultaneous spray method in which the drug and the polymer are dissolved in different solvents and sprayed onto the stent simultaneously from two nozzles. Although applicable, a method in which a coating layer of a polymer in which a drug is dispersed (including molecular dispersion) is formed on the stent surface is preferable because the release rate of the drug can be easily controlled. Especially, it is preferable that the chemical | medical agent (argatroban) is micro-dispersed in a polymer in the 1st composition which forms a 1st coating layer so that it may mention later.

(First coating layer and second coating layer)
The basic structure of the stent of the present invention includes (a) a stent body, (b) a first covering layer formed on at least the outer surface of the stent body and containing a polymer and a drug (preferably argatroban), and (c) It is comprised from the 2nd coating layer which contains less than 20 weight% of polymer alone or chemical | medical agent formed on the 1st coating layer as a weight component ratio with respect to 80 weight% of polymers. The first coating layer is loaded with a drug (argatroban) at a high concentration (maintained by molecular dispersion in the polymer or micro-dispersion in the order of nanometers or submicron order particles), and the second coating layer In addition, sustained release is provided over a long period of time by suppressing the release of the drug (argatroban). By selecting the thickness of the first coating layer, the loading state of the drug (argatroban) in the polymer in the first coating layer, the thickness of the second coating layer, the polymer composition in the second coating layer, the tissue, etc. Argatroban) release rate is controlled. For this reason, the second coating layer needs to be formed so as to substantially completely cover the first coating layer.

(First composition for forming the first coating layer)
As described above, the first covering layer is formed from the first composition containing the polymer and the drug (argatroban). The weight composition ratio of the polymer and the drug (argatroban) in the first composition is 8 to 3 for the polymer and 2 to 7 for the drug (argatroban), and the ratio of the drug (argatroban) is less than 2 The drug (argatroban) release rate from the coat layer is too small, and if it exceeds 7, the coat layer becomes brittle and it is difficult to adhere to the stent substrate. In addition to the polymer and the drug (argatroban), the first composition contains a release aid (carboxylic acid ester, monoester of glycerin, diester, preferably dimethyl tartrate, diethyl tartrate, etc.) disclosed in Patent Document 2. You may go out. In the first composition, as described above, the polymer (argatroban) can be released over a long period of time because the polymer carries the drug (argatroban) at a high concentration. Therefore, it is preferable that the first composition does not contain any drug other than the intimal thickening inhibitor (argatroban) so as not to inhibit the loading of the polymer drug (argatroban) of the first composition. In the first composition, whether the drug (argatroban) is microdispersed or molecularly dispersed in the polymer can be confirmed by the presence or absence of a crystal melting heat peak by differential thermal analysis (yes: microdispersion, no: molecular dispersion). .

(Supported state of drug (argatroban) in the first composition)
As described above, it is important that the release of the drug (argatroban) from the stent is maintained even after a predetermined period of time has elapsed after being inserted into the blood, particularly into an artery, but in the stent of the present invention, 37 The release rate of the drug (argatroban) on the first and second days from the time of immersion of the stent in phosphate buffered saline at 0 ° C. is adjusted to be 3 μg / cm ² · day or more. In order for the release rate of the drug (argatroban) to be as described above, the drug (argatroban) in the first composition is microscopic as described above rather than being dissolved or molecularly dispersed in the polymer. It is preferably dispersed (micro-dispersed in the form of particles of nanometer and submicron order). When the drug (argatroban) is dissolved in the polymer of the first composition, it is difficult to cause a necessary amount to be released within a predetermined period through the second coating layer. In the first composition, it is effective for controlling the release rate of the drug (argatroban) to keep the drug (argatroban) in a supported state so that the second coating layer has a predetermined release rate. It is.

(Polymer constituting the first composition)
In the present invention, the main objective is to continuously release a drug (argatroban) in an amount effective for stenosis suppression for a certain period of time. Therefore, in the first composition, as a matrix polymer for supporting the drug (argatroban) It is preferable to use a flexible polymer having a glass transition temperature (Tg) within the range of −100 to 50 ° C. in which the drug (Argatroban) can easily move in the polymer layer by diffusion. As such a flexible polymer, silicone rubber, urethane rubber, fluororesin, polybutyl acrylate (−54 ° C.), polybutyl methacrylate (20 ° C.), acrylic rubber, natural rubber, ethylene-vinyl acetate copolymer, styrene- Examples thereof include a butadiene block copolymer, a styrene-isoprene block copolymer, and a styrene-isobutylene block copolymer. The above-mentioned flexible polymer is non-degradable when introduced into a blood vessel, but in the present invention, when it is required to recover vascular tissue early from chronic inflammation caused by the polymer, It is preferable to coat with a degradable polymer, especially one that degrades and disappears in vivo within half a year. Specific examples of the biodegradable polymer include polylactic acid, poly (lactic acid-glycolic acid), polyglycolic acid, poly (lactic acid-ε-caprolactone), poly (glycolic acid-ε-caprolactone), poly-p-dioxanone, Examples include poly (glycolic acid-trimethylene carbonate), poly-β-hydroxybutyric acid, and the like. Among them, poly (lactic acid-glycolic acid), poly (lactic acid-ε-caprolactone), and poly (glycolic acid-ε-caprolactone) have a glass transition temperature in the range of −20 to 50 ° C. and have a biodegradation rate. It is preferably used in the present invention because it is a rate of degradation and disappearance in vivo within half a year. The molecular weight of these polymers is suitably 20,000 to 500,000 from the viewpoint of ensuring the strength of the coating layer and the coating work efficiency.

(Polymer selection and drug release rate)
In general, the drug release rate from the coat layer depends on the diffusion rate of the drug in the polymer for non-degradable polymers, but depends on the diffusion rate of the drug and the degradation rate of the polymer for biodegradable polymers. Therefore, in order to control the drug release rate, the type of polymer may be appropriately selected, and different types of polymers may be combined as necessary. Therefore, the drug release rate can be controlled by adjusting two parameters, the diffusion rate of the drug in the polymer and the degradation rate of the polymer. To increase the diffusion rate of the drug in the polymer, it is appropriate to select a rubbery polymer, and to increase the biodegradability rate, to select a copolymer having a high copolymerization ratio of glycolic acid. Is appropriate.

(Selection of biodegradable polymer and drug release rate)
When a biodegradable polymer is used as the polymer of the first composition, among the above biodegradable polymers, poly (lactic acid-glycolic acid) (copolymerization ratio = 100: 0 to 0: 100), poly (lactic acid) -Ε-caprolactone) (copolymerization ratio = 100: 0 to 25:75) is preferable in terms of safety since it has been used for the human body. Since the degradation rate of the biodegradable polymer depends on the chemical structure of the monomer constituting the polymer, the copolymerization ratio, and the molecular weight, it is preferable to adjust these parameters so as to suit the target drug release rate. In the case of poly (lactic acid-glycolic acid), increasing the ratio of glycolic acid increases the degradation rate, and the copolymer with a molar ratio of 50:50 degrades and disappears in about 3 months in vivo. With such polymers, drug release is completed within 2 months.

(Adjustment of drug release rate by addition of dissolution aid)
The first composition is composed of the polymer and the drug (argatroban) as described above. Furthermore, if necessary, the dissolution rate can be increased by blending an elution aid as the third component in the composition. Can be fast. As disclosed in Patent Document 2, elution aids that can be suitably used in the present invention are dimethyl tartrate and diethyl tartrate. These elution aids can be used alone or in combination of two. As a preferred embodiment for adjusting the drug (argatroban) release rate, dimethyl tartrate and / or diethyl tartrate may be added to the biodegradable polymer coat layer. The addition amount may be appropriately set according to the drug (argatroban) release rate, but is preferably within the range of about 5 to 60 phr of the polymer weight. When it is within this range, a good additive effect can be obtained.

(Thickness of the first coating layer)
The thickness of the coat layer per unit surface area (1 cm ² ) of the stent needs to be in the range of 1 to 25 μm from the viewpoint of releasing an appropriate amount of drug (argatroban). Usually, it is preferably in the range of 2 to 20 μm. If the coating layer including the second coating layer exceeds 20 μm, the in-stent stenosis may be increased. Therefore, it is preferable that the thickness of the first coating layer does not exceed 15 μm. Therefore, the coating liquid composition and the coating conditions are selected so that these application conditions can be satisfied. The first coating layer may be formed of a single layer, or may be formed of a plurality of layers within the above range.

(Second composition)
The second coating layer may be formed by polymer alone, as components other than the polymer, anti-intoxicated bottle drug (argatroban or the like), immunosuppressive agents (rapamycin, everolimus, biolimus A9, zotarolimus, tacrolimus, etc.), anti The composition may contain a drug such as a cancer drug (such as paclitaxel) or a cholesterol-lowering drug (such as a statin) within a range of less than 20% by weight based on 80% by weight of the polymer. In addition, elution aids such as dimethyl tartrate and diethyl tartrate, and components such as saccharides, polysaccharides, amino acids, inorganic / organic salts, and proteins such as biological components are drugs (argatroban) from the first coating layer to the second coating layer. 20% by weight because it is useful for controlling the rate of permeation through the (topcoat layer) and, in some cases, for inhibiting platelet aggregation, inhibiting thrombus formation, inhibiting smooth muscle proliferation, and promoting healing of vascular endothelium. An appropriate amount may be added within a range not exceeding.

(Polymer constituting the second coating layer)
In the present invention, the polymer alone or the second coating layer (topcoat layer) made of the second composition is coated on the first coating layer (basecoat) made of the first composition, and the drug from the first coating layer is coated. Controls release rate and imparts sustained release. As a component of the second composition, it is preferable to use a substance that can move the drug (argatroban) through the topcoat layer at an appropriate speed by diffusion. A material satisfying this condition is preferably a flexible polymer having a molecular weight of 10,000 to 500,000 and a glass transition temperature of −100 ° C. to 60 ° C. Specific examples of such polymers include silicone rubber, urethane rubber, fluororesin, polybutyl acrylate (−54 ° C.), polybutyl methacrylate (20 ° C.), acrylic rubber, natural rubber, ethylene-vinyl acetate copolymer, styrene- Nondegradable polymers such as a butadiene block copolymer, a styrene-isoprene block copolymer, and a styrene-isobutylene block copolymer are exemplified. When it is required to recover the vascular tissue early from the chronic inflammation caused by the polymer, it is preferable to use a biodegradable polymer, and more preferably one that degrades and disappears in vivo within half a year. Specific examples of the biodegradable polymer used in the present invention include polylactic acid, poly (lactic acid-glycolic acid), polyglycolic acid, poly (lactic acid-ε-caprolactone), poly (glycolic acid-ε-caprolactone), poly -P-dioxanone, poly (glycolic acid-trimethylene carbonate), poly-β-hydroxybutyric acid, etc., among others, poly (lactic acid-glycolic acid), poly (lactic acid-ε-caprolactone), poly (glycolic acid) -Ε-caprolactone) is preferably used in the present invention because it has a glass transition temperature in the range of −20 to 60 ° C. and decomposes and disappears in vivo within half a year. The molecular weight of these polymers is suitably in the range of 10,000 to 500,000 from the viewpoint of ensuring the strength of the second coating layer and the coating work efficiency. The polymer of the second coating layer and the polymer of the first coating layer may be the same or different.

(The thickness of the second coating layer)
The film thickness of the second coating layer is preferably in the range of 0.5 to 5 μm. If it is less than 0.5 μm, the uniformity of the film cannot be ensured, and the function of suppressing the drug (argatroban) release rate cannot be exhibited. Conversely, if the thickness exceeds 5 μm, there is a risk that the drug (argatroban) release rate will be too slow. The second coating layer may be a single layer or may be formed of a plurality of layers within the above range.

(Formation method of a 1st coating layer)
In order to coat the surface of the stent body with a matrix polymer carrying a drug (argatroban), a solution in which the drug and polymer are dissolved in a volatile solvent (eg, fluorinated alcohol) is sprayed on the stent surface, or the stent body Is immersed in the solution, applied to the stent body, and dried. In the present invention, the first composition containing a drug (argatroban) is coated on at least the outer surface (the surface in contact with the blood vessel wall) of the cylindrical stent body. In this case, the application is preferably performed by spraying a solution obtained by dissolving the first composition in a solvent on the outer surface of the stent body. Further, when the treatment is performed not only on the outer surface but also on the inner surface, it is preferable to spray both the inner and outer surfaces or impregnate the stent body in the solution. The removal of the solvent after coating is appropriately performed by a method such as decompression, air blowing, and heating.

(Stent treatment of the stent body)
When coating the above coating solution on the stent surface, the coating layer that remains after the solvent volatilizes needs to adhere to the stent surface, so the surface of the stent body should be washed or surface-activated as necessary before the coating operation. It is preferable to perform the conversion process. Examples of the surface treatment method include chemical treatment with an oxidizing agent and fluorine gas, surface graft polymerization, plasma discharge treatment, corona discharge treatment, UV / ozone treatment, and electron beam irradiation.

(Selection of solvent for forming the first composition)
Examples of volatile solvents having a boiling point of less than 100 ° C. that can dissolve the drug (argatroban) and can be easily removed after coating include methanol, ethanol, trifluoroethanol, hexafluoroisopropanol, and mixed solvents containing these alcohols. It is done. As the polymer, the polymers exemplified above are used. Among them, poly (lactic acid-glycolic acid) and poly (lactic acid-ε-caprolactone) having high polarity are preferable from the viewpoint of solubility in the above solvent. Solvents suitable for dissolving both the drug (argatroban) and the above-mentioned polymer and providing sustained release of the drug include trifluoroethanol and hexafluoroisopropanol, as well as lower solvents such as ethyl acetate, methyl acetate, and butyl acetate. Mixed solvent of alkyl ester (carbon number: 6 or less) and methanol, mixed solvent of lower alkyl ketone (carbon number: 6 or less) and methanol such as acetone, methyl ethyl ketone, lower halogenated hydrocarbon such as methylene chloride, chloroform, dichloroethane ( Examples thereof include a mixed solvent of carbon number: 4 or less) and methanol. Among them, from the viewpoint of giving a drug (argatroban) micro-dispersed in a polymer to give sustained drug release properties, a mixed solvent of a lower alkyl ester and methanol, a mixed solvent of a lower alkyl ketone and methanol, and a lower halogenated hydrocarbon and methanol. Mixed solvents are preferred. When the coating layer is formed using these mixed solvents and the solvent is removed, the drug (argatroban) is supported in a micro-dispersed state on the polymer, and when the second coating layer is formed thereon, the drug ( Argatroban) release rate would be desirable.

(Formation of second coating layer)
A 2nd coating layer is formed by apply | coating the solution which melt | dissolved the polymer in the solvent or the solution which melt | dissolved the 2nd composition which consists of a polymer and another structural component on a 1st coating layer. The application method is the same as the formation of the first coating layer.

(Formation of second composition)
As the solvent for forming the polymer that forms the second coating layer or the second composition containing the polymer and other components, the solvent that forms the first composition can be used, but it does not dissolve argatroban. The method of coating the polymer and other components with a solvent (lower alkyl ester, lower alkyl ketone, lower halogenated hydrocarbon, etc.) that dissolves is preferable in that the drug release rate can be precisely controlled. In this case, the second composition does not contain argatroban.

(Adjustment of drug release rate)
In order for the drug sustained-release stent of the present invention to remarkably suppress in-stent stenosis, as is apparent from the animal test results described in the Examples (including Reference Examples) section, the phosphate buffered physiology at 37 ° C. Argatroban is 3 μg / cm ² · day or more, preferably 4 μg / cm ² · day or more, more preferably 6 μg / cm ² · day or more for at least 2 days after immersing the stent in saline (pH 7.4). The inventor has found that the release rate needs to be adjusted to release at a rate. The upper limit of the release rate is not necessarily clear from the viewpoint of the effect of suppressing stenosis, but if the amount of the drug is too large, there is a risk of causing side effects such as bleeding, and the use of an excessive amount of the drug is a point of manufacturing cost. Therefore, 500 μg / cm ² · day, usually 300 μg / cm ² · day is appropriate. The release rate after the third day is not an essential condition for suppressing in-stent stenosis, but since continuous argatroban release after the third day is expected to further enhance the stenosis-inhibiting effect, 2 μg / It is desirable that the drug release rate of cm ² · day or more continues for 1-2 weeks after the third day. The drug-coated layer according to the present invention is particularly preferred as a method for releasing the argatroban at a rate of 3 μg / cm ² · day or more for the first at least two days after the stent is placed in the artery. That is, a first composition comprising 20 to 70% by weight of argatroban and 80 to 30% by weight of polymer is uniformly coated on the outer surface of the cylindrical stent body within a thickness range of 1 to 15 μm, and The polymer alone or the polymer and the drug are included so as to substantially completely cover the surface of the first coating layer formed from the first composition, and the weight composition ratio of the drug with respect to 80% by weight of the polymer is less than 20% by weight. For stents that are uniformly coated with a second coating layer comprising the second composition, the release rate of argatroban is at least 2 days after immersing the stent in 37 ° C. phosphate buffered saline (pH 7.4). during the argatroban 3 [mu] g / cm ² · day or more, preferably 4 [mu] g / cm ² · day or more, more preferably released at 6 [mu] g / cm ² · day or faster It can be realized by adjusting the so that the release rate.

  The release rate of the drug (argatroban) is such that the drug (argatroban) is supported at a high concentration in the polymer of the first composition, and the second coating layer contains the polymer alone or the drug in a small amount of less than 20% by weight. When the dense polymer layer formed from the product is present in a thickness range of 0.5 to 5 μm, the release of the drug (argatroban) contained in the first coating layer is suppressed, thereby providing sustained release. In particular, in the first coating layer, it is preferable that the drug (argatroban) is supported on the polymer in a microdispersed state. In order to support the drug (argatroban) in a microdispersed state, it is possible to select the solvent used when preparing the composition containing the polymer and the drug (argatroban) as described above.

  The release rate of the drug (argatroban) is affected by the polymer constituting the first composition and the second coating layer, but can be controlled by changing the thickness of the coating layer within the above range depending on the polymer used. . Of these, a copolymer of lactic acid and glycolic acid is preferable.

( Reference Example )
Hereinafter, the present invention will be specifically described with reference to an example using argatroban as an intimal thickening inhibitor, but these examples are not intended to limit the present invention. The materials used in the examples, the amount used, the concentration, the numerical conditions such as the processing temperature, the processing method and the like are only suitable examples within the scope of the present invention.

[Production Example 1]
A uniform solution (coating solution) was prepared by dissolving 140 mg of argatroban and 160 mg of poly D, L-lactic acid / glycolic acid copolymer (molar ratio: 50/50) in 20 mL of 2,2,2-trifluoroethanol. 1 is a mandrel of a spray-type coating device having a stent body (referred to as Stent1) having an outer diameter of 1.55 mmΦ, a post-expansion inner diameter = 3 mmΦ, a length of 17 mm, and a total surface area = 0.70 cm ² having the design shown in FIG. Attached to. The coating liquid is sprayed from the nozzle at a speed of 20 μL / min, and the stent body is reciprocated while rotating at a speed of 120 revolutions per minute at a position 9 mm below the nozzle, and from the end to the center of the stent body for about 4 minutes. The surface was coated. The stent was dried under nitrogen flow for 10 minutes after the coating was completed, and then the other half was coated. The stent having been fully coated was air-dried for about 1 hour and then dried at 60 ° C. for 17 hours in a vacuum thermostatic dryer to completely remove the solvent. 30 stent bodies were coated under the same conditions. When weighed to the unit of μg with a precision balance, the obtained stent was coated with an average of 619 μg of the mixture of argatroban and the copolymer (average first coating layer thickness 7.4 μm). Hereinafter, this stent is referred to as DES1.

[Production Example 2]
300 mg of poly D, L-lactic acid / glycolic acid copolymer (molar ratio: 50/50) was dissolved in 20 mL of chloroform to prepare a uniform solution (coating solution). DES1 produced in Production Example 1 was attached to a mandrel of a spray type coating apparatus. The coating solution is sprayed from the nozzle at a speed of 20 μL / min, and the stent is reciprocated while rotating at a speed of 120 revolutions per minute at a position of 9 mm below the nozzle to reach the surface from the end to the center of the stent for about 100 seconds. Coating was performed. The stent was dried under nitrogen flow for 10 minutes after the coating was completed, and then the other half was coated. The stent having been fully coated was air-dried for about 1 hour and then dried at 60 ° C. for 17 hours in a vacuum thermostatic dryer to completely remove the solvent. 15 stents were coated under the same conditions. The stent obtained by weighing with a precision balance was coated with an average of 103 μg of the copolymer (average thickness of the second coating layer: 1.2 μm). Hereinafter, this two-layer-coated stent (total coating amount of 722 μg, average coating layer thickness of 8.6 μm) is referred to as DES2.

[Production Example 3]
120 mg of argatroban and 180 mg of poly D, L-lactic acid / glycolic acid copolymer (molar ratio: 50/50) were dissolved in 20 mL of 2,2,2-trifluoroethanol to prepare a uniform solution (coating solution). The Stent 1 was mounted on a mandrel of a spray type coating apparatus. The coating liquid is sprayed from the nozzle at a speed of 20 μL / min, and the stent body is reciprocated while rotating at a speed of 120 revolutions per minute at a position 9 mm below the nozzle, and from the end to the center of the stent body for about 4 minutes. The surface was coated. The stent was dried under nitrogen flow for 10 minutes after the coating was completed, and then the other half was coated. The stent having been fully coated was air-dried for about 1 hour and then dried at 60 ° C. for 17 hours in a vacuum thermostatic dryer to completely remove the solvent. 30 stent bodies were coated under the same conditions. When weighed to the unit of μg with a precision balance, the resulting stent was coated with an average of 493 μg of a mixture of argatroban and the copolymer (average first coating layer thickness 5.9 μm). Hereinafter, this stent is referred to as DES3.

[Production Example 4]
300 mg of poly D, L-lactic acid / glycolic acid copolymer (molar ratio: 50/50) was dissolved in 20 mL of chloroform to prepare a uniform solution (coating solution). DES3 was mounted on a mandrel of a spray coating apparatus. The coating solution is sprayed from the nozzle at a speed of 20 μL / min, and the stent is reciprocated while rotating at a speed of 120 revolutions per minute at a position of 9 mm below the nozzle to reach the surface from the end to the center of the stent for about 100 seconds. Coating was performed. The stent was dried under nitrogen flow for 10 minutes after the coating was completed, and then the other half was coated. The stent having been fully coated was air-dried for about 1 hour and then dried at 60 ° C. for 17 hours in a vacuum thermostatic dryer to completely remove the solvent. 15 stents were coated under the same conditions. The stent obtained by weighing with a precision balance was coated with an average of 148 μg of the copolymer (average thickness of the second coating layer: 1.8 μm). Hereinafter, this bilayer-coated stent (total coating amount 641 μg, average coating layer thickness 7.6 μm) is referred to as DES4.

[Production Example 5]
120 mg of argatroban and 180 mg of poly-D, L-lactic acid were dissolved in 20 mL of an acetone / methanol mixed solvent (volume ratio: 7: 3) to prepare a uniform solution (coating solution). The Stent 1 was mounted on a mandrel of a spray type coating apparatus. The coating liquid is sprayed from the nozzle at a speed of 20 μL / min, and the stent body is reciprocated while rotating at a speed of 120 revolutions per minute at a position 9 mm below the nozzle, and from the end to the center of the stent body for about 4 minutes. The surface was coated. The stent was dried under nitrogen flow for 10 minutes after the coating was completed, and then the other half was coated. The stent having been fully coated was air-dried for about 1 hour and then dried at 60 ° C. for 17 hours in a vacuum thermostatic dryer to completely remove the solvent. 30 stents were coated under the same conditions. When weighed to the microgram unit with a precision balance, the resulting stent was coated with an average of 583 micrograms of a mixture of argatroban and the copolymer. Hereinafter, this stent (average first coating layer thickness 6.9 μm) is referred to as DES5.

[Production Example 6]
300 mg of poly D, L-lactic acid / glycolic acid copolymer (molar ratio: 50/50) was dissolved in 20 mL of ethyl acetate to prepare a uniform solution (coating solution). DES5 was mounted on a mandrel of a spray coating apparatus. The coating solution is sprayed from the nozzle at a speed of 20 μL / min, and the stent is reciprocated while rotating at a speed of 120 revolutions per minute at a position of 9 mm below the nozzle to reach the surface from the end to the center of the stent for about 100 seconds. Coating was performed. The stent was dried under nitrogen flow for 10 minutes after the coating was completed, and then the other half was coated. The stent having been fully coated was air-dried for about 1 hour and then dried at 60 ° C. for 17 hours in a vacuum thermostatic dryer to completely remove the solvent. 15 stents were coated under the same conditions. When weighed to the unit of μg with a precision balance, the obtained stent was coated with an average of 255 μg of the copolymer mixture (average second film thickness of 3.0 μm). Hereinafter, this two-layer coated stent (total coating amount 838 μg, average covering layer thickness 10.0 μm) is referred to as DES6.

[Production Example 7]
300 mg of poly D, L-lactic acid / glycolic acid copolymer (molar ratio: 50/50) was dissolved in 20 mL of 2,2,2-trifluoroethanol to prepare a uniform solution (coating solution). Stent 1 was mounted on a mandrel of a spray coating apparatus. The coating liquid is sprayed from the nozzle at a speed of 20 μL / min, and the stent body is reciprocated while rotating at a speed of 120 revolutions per minute at a position 9 mm below the nozzle, and from the end to the center of the stent body for about 4 minutes. The surface was coated. The stent was dried under nitrogen flow for 10 minutes after the coating was completed, and then the other half was coated. The stent having been fully coated was air-dried for about 1 hour and then dried at 60 ° C. for 17 hours in a vacuum thermostatic dryer to completely remove the solvent. Ten stents were coated under the same conditions. When weighed to the microgram unit with a precision balance, the resulting stent was coated with an average of 487 micrograms of the copolymer. Hereinafter, this stent (average covering layer thickness 5.8 μm) is referred to as PCS1.

<Drug release test 1>
The drug release rates from the six types of drug-coated stents shown in Production Examples 1 to 6 were measured. Each stent was mounted on a balloon catheter having a diameter of 3 mm and a length of 20 mm, and sterilized with ethylene oxide gas (EOG). After sterilization, the balloon catheter was pressurized at about 12 atmospheres for 30 seconds, and the stent was expanded to a diameter of 3 mm. Three stents were placed in a clean sealed glass container and 30 mL of pH 7.4 phosphate buffered saline was added. The whole stent was immersed in the liquid and shaken in a 37 ° C. incubator.

The UV absorption (331 nm) of the eluate was measured with a UV-visible spectrophotometer UV-2450 (manufactured by Shimadzu) every predetermined time, and the absorbance of argatroban was measured. A calibration curve was prepared using phosphate buffered saline with a concentration of 0.001% and 0.0001% of argatroban, and the absorbance was converted into a concentration, and the amount of argatroban released per cm ^{2 of the} eluted stent surface area was determined. The results are shown in Table 1.

From Table 1, the drug-coated stents coated with two layers (DES2, DES4, and DES6) did not show any burst-like rapid release within 24 hours of immersion, and the release of argatroban between 24 and 48 hours of immersion. The amount was 4 μg / cm ² · day or more, indicating the release of argatroban.

<Animal test 1>
Drug releasing stents prepared in Production Example 1, 2, 4, 6, PCS1 subjected only polymer coating DES1,2,4,6 and preparations 7, S t 6 types of stents each six ent1, total 36 The book was implanted in 18 coronary arteries (LAD, LCX) of crown minipigs (weight 25-40 kg), and the degree of in-stent stenosis was evaluated by quantitative coronary angiography (QCA) after 1 month.

  Each stent was mounted on a balloon catheter and EOG sterilization was performed. Each stent was inserted into the coronary artery using a 6Fr guiding catheter from the right femoral artery of a minipig under general anesthesia using a sheath introducer. Select the implantation site and the stent expansion pressure so that the vessel diameter (proximal part) after stent implantation is within the range of 1.0 to 1.2 relative to the original vessel diameter. I planted. Aspirin 100 mg and clopidogrel 50 mg were mixed and administered for 33 days from 3 days before implantation to stent extraction.

30 days after implantation, the diameter of the blood vessel lumen at the stent implantation site was measured at three locations, the proximal portion, the central portion, and the distal portion of the stent. The stenosis rate was calculated by the following formula.
Vessel diameter stenosis rate = (lumen diameter immediately after implantation-lumen diameter after one month) / lumen diameter immediately after implantation x 100
Table 2 shows the calculated average vessel diameter stenosis rate (%).

As can be seen from Table 2, the stenosis rate is smaller in DES4 (Example 2) where the amount of drug released during 24 to 48 hours is 4 μg / cm ² · day or more than in Stent1 (Comparative Example 3). On the other hand, DES1 (Comparative Example 1) of 1 μg / cm ² · day or less shows almost the same stenosis rate as PCS1 (Comparative Example 2) containing no drug, and no stenosis-inhibiting effect is observed at all. The stenosis rate is larger than Stent 1 (Comparative Example 3) of the stent, and only an adverse effect due to the polymer coating appears.

<Animal test 2>
Six stents (DES2) produced in Production Example 2 and six stents (DES5) produced in Production Example 5 (Comparative Example 4) were made into six coronary arteries (LAD, LCX) 12 in a crown-type minipig (weight 25-36 kg). The book was implanted according to the procedure of animal test 1, and the heart excised after 28 days of pathological dissection was fixed with formalin. The blood vessel tissue in which the stent was implanted was cut out from the heart, fixed with acrylic resin, and then cut at three locations at the center and both ends of the stent to prepare a thin section having a thickness of 6 μm. These were stained with hematoxylin and eosin staining and elastica-Wangeson staining, and the area stenosis rate (%) and the endothelial cell coverage rate (%) were evaluated. In DES2, the area stenosis rate was 28 ± 8%, which almost coincided with the average vessel diameter stenosis rate in Example 1. Endothelial cell coverage was 100%, and damage to the inner wall of the blood vessel at the time of stent implantation was completely healed. In DES5, the area stenosis rate was 64 ± 16%, which almost coincided with the average blood vessel diameter stenosis rate of Comparative Example 1 and Comparative Example 2. For comparison, an example of a pathological specimen of DES2 is shown in FIG. 2, and an example of a pathological specimen of DES5 is shown in FIG.

Argatroban supported on the surface of the arterial stent is in a phosphate buffered saline (pH 7.4) at 37 ° C. at a rate of ^{3 to} 300 μg / cm ² · day for at least 2 days from the time of immersion of the stent. A drug sustained-release arterial stent was created in which the release rate of argatroban was controlled to be released. When this is placed in the artery, the released argatroban can effectively suppress intimal thickening, and the inner wall of the blood vessel is almost completely covered with endothelial cells within one month of stent placement. And from the results of animal experiments.

[Reference Production Example 1]
Dissolve 140 mg of argatroban and 160 mg of poly D, L-lactic acid / glycolic acid copolymer (molar ratio: 65/35) in 20 mL of an acetone / methanol mixed solvent (volume ratio = 7: 3) to obtain a uniform solution (coating solution). Prepared. A cobalt alloy stent having the same shape as the Stent 1 and coated with a diamond-like thin film was plasma-discharge treated, and then mounted on a mandrel of a spray coating apparatus. The coating liquid is sprayed from the nozzle at a speed of 20 μL / min, and the stent body is reciprocated while rotating at a speed of 120 revolutions per minute at a position 9 mm below the nozzle, and from the end to the center of the stent body for about 4 minutes. The surface was coated. The stent was dried under nitrogen flow for 10 minutes after the coating was completed, and then the other half was coated. The stent having been fully coated was air-dried for about 1 hour and then dried at 60 ° C. for 17 hours in a vacuum thermostatic dryer to completely remove the solvent. Ten stent bodies were coated under the same conditions. When weighed to the unit of μg with a precision balance, the resulting stent was coated with an average of 643 μg of the mixture of argatroban and the copolymer (average first coating layer thickness 7.7 μm). Hereinafter, this stent is referred to as DES7.

[Reference Production Example 2]
150 mg of poly D, L-lactic acid / glycolic acid copolymer (molar ratio: 65/35) was dissolved in 20 mL of the acetone-methanol mixed solvent to prepare a uniform solution (coating solution). DES7 produced in Production Example 8 was attached to a mandrel of a spray type coating apparatus. The coating liquid is sprayed from the nozzle at a speed of 20 μL / min, and the stent is reciprocated while rotating at a speed of 120 revolutions per minute at a position 9 mm below the nozzle to reach the surface from the end to the center of the stent for about 180 seconds. Coating was performed. The stent was dried under nitrogen flow for 10 minutes after the coating was completed, and then the other half was coated. The stent having been fully coated was air-dried for about 1 hour and then dried at 60 ° C. for 17 hours in a vacuum thermostatic dryer to completely remove the solvent. Ten stents were coated under the same conditions. The stent obtained by weighing with a precision balance was coated with an average of 241 μg of the copolymer (thickness: 2.9 μm). Hereinafter, this two-layer-coated stent (total coating amount 884 μg, average covering layer thickness 10.5 μm) is referred to as DES8.

[Reference Example]
<Reference drug release test>
The drug release rate from the drug-coated stent shown in Reference Production Example 2 was measured. Each stent was mounted on a balloon catheter having a diameter of 3 mm and a length of 20 mm, and sterilized with ethylene oxide gas (EOG). After sterilization, the balloon catheter was pressurized at about 12 atmospheres for 30 seconds, and the stent was expanded to a diameter of 3 mm. Three stents were placed in a clean sealed glass container and 30 mL of phosphate buffered saline at pH 7.4 was added. The whole stent was immersed in the liquid and shaken in a 37 ° C. incubator.

The UV absorption (331 nm) of the eluate was measured with a UV-visible spectrophotometer UV-2450 (manufactured by Shimadzu) every predetermined time, and the absorbance of argatroban was measured. A calibration curve was prepared using phosphate buffered saline of 0.001% and 0.0001% argatroban, and the absorbance was converted into a concentration, and the amount of argatroban released per 1 cm ² of the released stent surface area was determined. The results are shown in Table 3.

From Table 3, in the two-layer coated drug-coated stent (DES8), no burst-like rapid release within 24 hours of immersion was observed, and the release amount of argatroban was 46 μg during 24 to 48 hours of immersion. / Cm ² · day or more, indicating release of argatroban.

[Examples 4 to 7]
30 mg of argatroban and 90 mg of poly D, L-lactic acid / glycolic acid copolymer (molar ratio: 65/35) were dissolved in 5 mL of four organic solvents shown in Table 4 and cast onto a glass plate. This was air-dried at room temperature for 6 hours and then vacuum-dried at 60 ° C. for 17 hours to recover a polymer film containing argatroban. This film was thermally analyzed by a DSC apparatus (differential scanning calorimetry). The temperature was raised from room temperature to 210 ° C. at a rate of 5 ° C. per minute, and the crystal melting temperature (endothermic peak temperature) of argatroban was measured. The results are shown in Table 4. In the coating using 2,2,2, -trifluoroethanol, no endothermic peak appeared between room temperature and 210 ° C., and it was assumed that argatroban was molecularly dispersed in the polymer. On the other hand, when an acetone-methanol mixed solvent, an ethyl acetate-methanol mixed solvent, and a 1,2, dichloroethane-methanol mixed solvent were used, an endothermic peak due to crystal melting of argatroban appeared around 178 ° C. From this, it was found that there was a difference in the dispersion state of argatroban incorporated into the polymer depending on the solvent used.

The cast film was cut into 3 cm ² pieces on the surface and 30 mL of phosphate buffered saline at pH 7.4 was added. The whole stent was immersed in the liquid and shaken in a 37 ° C. incubator. The UV absorption (331 nm) of the eluate from the 2nd day to the 7th day after the start of immersion was measured with an ultraviolet-visible spectrophotometer UV-2450 (manufactured by Shimadzu), and the absorbance of argatroban was measured. A calibration curve was prepared using phosphate buffered saline of 0.001% and 0.0001% argatroban, and the absorbance was converted into a concentration, and the amount of argatroban released per 1 cm ² of the released stent surface area was determined. The results are shown in Table 4. Compared to Example 4 where no endothermic peak appeared, the amount of argatroban released in Examples 5, 6 and 7 where an endothermic peak appeared was 10 times or more.

<Reference animal test>
Ten stents (DES8) produced in Reference Production Example 2 and ten commercially available drug release stents “Cyper” (Johnson & Johnson Co., Ltd.) using rapamycin (immunosuppressive agent) as an intimal thickening inhibitor Were implanted into 20 coronary arteries (LAD, LCX, RCA) of 20 crown minipigs (weight 27-43 kg) according to the procedure of animal test 1, and the heart excised by pathological dissection 90 days later was fixed with formalin. The blood vessel tissue in which the stent was implanted was cut out from the heart, fixed with acrylic resin, and then cut at three locations at the center and both ends of the stent to prepare a thin section having a thickness of 6 μm. These were stained with hematoxylin and eosin staining and elastica-Wangeson staining, and the area stenosis rate (%) and the endothelial cell coverage rate (%) were evaluated. In DES8, the area stenosis rate was 30 ± 13%, the endothelial cell coverage was 100%, and the damage to the inner wall of the blood vessel at the time of stent implantation was completely healed. In Cypher, the area stenosis rate was 54 ± 22%, and the endothelial cell coverage was 95%.

  In the drug sustained-release stent of the present invention, the vascular endothelium was completely repaired one month after the stent was implanted in the minipig, but in Cypher, a part of the inner wall of the blood vessel was covered with endothelial cells even after 3 months. Was not.

  Although specific embodiments of the present invention have been described, it is clear that those skilled in the art can readily modify the above-described embodiments described herein. Therefore, the present invention is not limited to the specific embodiments shown in this specification, but can be applied to any other modifications, changes, and utilizations of the embodiments. All modifications, changes and embodiments should be considered as falling within the spirit and scope of the invention.

Claims (18)

A stent body formed in a cylindrical shape having an outer surface and an inner surface, the surface of which is not coated with a diamond thin film, a first coating layer covering at least the outer surface of the stent body, and the first coating A second covering layer covering the layer substantially completely,
The first coating layer includes a polymer and an intimal thickening inhibitor that does not inhibit endothelial cell growth, and the weight composition ratio of the polymer and the intimal thickening inhibitor is 8 to 3 in the polymer. Formed by the first composition in the range of the membrane thickening inhibitor 2-7,
The second covering layer is formed of a polymer alone or a stent including a polymer and a drug, and the second composition layer is formed of a second composition in which the weight composition ratio of the drug with respect to 80% by weight of the polymer is less than 20% by weight. .   The stent according to claim 1, wherein an essential component of the intimal thickening inhibitor is argatroban.   The stent according to claim 1, wherein the first covering layer has a thickness in the range of 1 to 20 µm, and the second covering layer has a thickness in the range of 0.5 to 5 µm.   The stent according to claim 2, wherein argatroban in the first coating layer is micro-dispersed in a polymer.   The stent according to claim 2, wherein the first coating layer does not contain a drug other than argatroban.   The stent according to claim 1, wherein the second covering layer is formed of a polymer alone.   2. The stent according to claim 1, wherein the drug of the second composition is argatroban, rapamycin, everolimus, biolimus A9, zotarolimus, tacrolimus, paclitaxel or statin.   The stent according to claim 1, wherein the polymer forming the first composition and / or the second coating layer is a biodegradable polymer.   9. The stent according to claim 8, wherein the biodegradable polymer is polylactic acid, poly (lactic acid-glycolic acid), polyglycolic acid, poly (lactic acid-ε-caprolactone), or poly (glycolic acid-ε-caprolactone).   The stent according to claim 1, wherein the stent body is formed of a metal material, a ceramic, or a polymer material. A stent body formed into a cylindrical shape having an outer surface and an inner surface, the surface of which is not coated with a diamond thin film;
A first coating layer having a thickness in the range of 1-15 μm, covering at least the outer surface of the stent body;
A second coating layer having a thickness in the range of 0.5 to 5 μm, covering the first coating layer so as to substantially completely cover the first coating layer,
The first covering layer includes a polymer and argatroban, and is formed of a first composition in which the weight composition ratio of the polymer and argatroban is in the range of polymer 8-3 to argatroban 2-7,
The second covering layer is formed of a polymer alone or a stent including a polymer and a drug, and the second composition layer is formed of a second composition in which the weight composition ratio of the drug with respect to 80% by weight of the polymer is less than 20% by weight. .   At least the outer surface of the stent body using a solution obtained by dissolving the first composition in claim 2 in a lower alkyl ketone-methanol mixed solvent, a lower alkyl ester-methanol mixed solvent, or a lower halogenated hydrocarbon-methanol mixed solvent. A method for manufacturing a stent in which the first coating layer is formed by removing the solvent after coating. The stent according to claim 2,
One day from the time of immersion of the stent in 37 ° C. phosphate buffered saline by selecting a predetermined thickness of the second coating layer within a range of 0.5 to 5.0 μm. A method for adjusting the release rate of argatroban from a stent, wherein the release rate of argatroban on the eye and the second day is adjusted to be 3 μg / cm ² · day or more, respectively. The stent according to claim 2,
By selecting a predetermined thickness within the range of 0.5 to 5.0 μm for the thickness of the second coating layer, two days from the time of immersion of the stent in 37 ° C. phosphate buffered saline A method for adjusting the release rate of argatroban from a stent, wherein the release rate of argatroban in the eye is adjusted to be in the range of 3 to 100 μg / cm ² · day. The stent according to claim 2,
By selecting a predetermined thickness within the range of 0.5 to 5.0 μm, the thickness of the second coating layer is 3 days from the time of immersion of the stent in 37 ° C. phosphate buffered saline. A method for adjusting the release rate of argatroban from a stent, characterized in that the release rate of argatroban from day 1 to day 7 is adjusted to be in the range of ^{2 to} 50 μg / cm ² · day.   16. The method for adjusting the release rate of argatroban from a stent according to claim 13, 14 or 15, wherein in the first composition, argatroban is microdispersed in a polymer to adjust the release rate of argatroban.   16. The solvent for dissolving the first composition according to claim 13, 14, or 15 is selected from a lower alkyl ester-methanol mixed solvent or a lower alkyl ketone-methanol mixed solvent, and the first composition depends on the selected solvent. From the argatroban stent, the surface of the stent body is coated using a solution in which an object is dissolved, and after the coating, the solvent is removed to form a first coating layer, thereby adjusting the release rate of argatroban. Method of adjusting the release rate of water.   16. The release rate of argatroban is controlled by changing the copolymerization ratio of lactic acid and glycolic acid, wherein the polymer of the second coating layer is a poly (lactic acid-glycolic acid) copolymer. A method for adjusting the release rate of the argatroban stent.

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